Clinical Pharmacokinetics[JOURNAL]
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200 papers
Population Pharmacokinetic Modelling of Dolutegravir: A Narrative Review.
Pilote É, Sheehan NL, Marsot A
Clin Pharmacokinet · 2026 Jun · PMID 42377866 · Publisher ↗
Dolutegravir-based regimens are part of the preferred regimens in all populations living with HIV, but dolutegravir's pharmacokinetics can vary greatly with factors such as drug-drug interactions (DDIs) and age. For exam...
Dolutegravir-based regimens are part of the preferred regimens in all populations living with HIV, but dolutegravir's pharmacokinetics can vary greatly with factors such as drug-drug interactions (DDIs) and age. For example, DDIs between dolutegravir and rifamycins in countries with a high burden of HIV/tuberculosis co-infection present a major challenge. Attaining therapeutic concentrations is crucial for virologic success and to prevent resistance. Understanding dolutegravir pharmacokinetics and its sources of variability is essential to ensure adequate exposure in all individuals. Population pharmacokinetic (PopPK) modeling is a powerful tool for characterizing medication disposition. In this review, we aim to synthesize existing dolutegravir PopPK models, highlighting key pharmacokinetic parameters and covariate effects. A literature search was done on Medline and Embase databases from inception to November 18th, 2025. This review included 23 studies: 15 in adults, 4 in pediatrics, 2 in pregnancy (mothers and their newborn), and 2 in term neonates. Almost all models included allometric scaling, with body weight especially, on apparent clearance (CL/F) and/or apparent volume of distribution (Vd/F) parameters. When considering differences in body size, CL/F and Vd/F were similar across populations. The absorption rate constant (k) was higher in adults and presented high variability across populations. Other common covariates in adults and pediatrics were co-medications and background antiretrovirals. Data and tested covariates were limited in pregnant women and neonates. Study simulations and predefined target values indicated adequate recommended dolutegravir doses. Further characterization of dolutegravir PopPK in populations at risk of altered concentrations (e.g., preterm neonates, pediatrics, pregnancy, obesity, and older adults) is crucial to better understand dolutegravir pharmacokinetics in these populations as data are still limited.
Partial Area Under the Curve: A Revelatory Story in Pharmacokinetics.
Periyasamy M, Ravichandran M
Clin Pharmacokinet · 2026 Jun · PMID 42373955 · Publisher ↗
Bioequivalence studies are important for a generic drug to enter the market. These studies mainly examine various pharmacokinetic parameters like C, AUC and AUC. But at times, these parameters might not be sufficient to...
Bioequivalence studies are important for a generic drug to enter the market. These studies mainly examine various pharmacokinetic parameters like C, AUC and AUC. But at times, these parameters might not be sufficient to pick up essential kinetics. It is even possible to undertake the additional parameter along with the traditional pharmacometrics. This article gives an overview of one such parameter, partial area under the curve (pAUC), which captures specific time intervals of clinical relevance. The pAUC is especially useful for comparing specific formulations, determining bioequivalence in early or late stages, and assessing medicines with time-dependent therapeutic windows. When employed correctly, pAUC improves our understanding of temporal drug behaviour beyond what total AUC can provide, allowing for more precise and clinically meaningful pharmacokinetic assessments. This article is a review that describes how pAUC has been used in specific regulatory guidelines for drug products that have time-dependent exposures, which may impact the drug's pharmacodynamic properties. These product guidances have been issued by the US Food and Drug Administration (FDA), Health Canada, and European Medicines Agency (EMA). This article presents various viewpoints about pAUC in the mindset of regulators, researchers, and industrial experts.
Informing Sampling Design for Lung Distribution Studies Using a Pulmonary Population Minimal PBPK Model.
Wen H, Sadiq MW, Fridén M … +3 more , Hohlfeld JM, Friberg LE, Svensson EM
Clin Pharmacokinet · 2026 Jun · PMID 42371390 · Publisher ↗
BACKGROUND: Understanding intrapulmonary pharmacokinetics (PK) following inhalation remains a significant challenge in drug development and repurposing. Current lung sampling methods include bronchoalveolar lavage (BAL),...
BACKGROUND: Understanding intrapulmonary pharmacokinetics (PK) following inhalation remains a significant challenge in drug development and repurposing. Current lung sampling methods include bronchoalveolar lavage (BAL), biopsies, and the more recent bronchosorption technique, which enhances regional specificity while reducing potential quantification errors. This study aimed to develop a pulmonary population physiologically based pharmacokinetic (PBPK) model for inhaled salbutamol by integrating data from all three sampling techniques to improve PK predictions and to compare different sampling strategies to optimize future study designs. METHODS: A population-based minimal PBPK model was developed using data from a previously published study (NCT03524066) investigating salbutamol's pulmonary and plasma PK in 13 healthy volunteers after inhalation. Simulations assessed the impact of permeability on pulmonary PK profiles and BAL-derived epithelial lining fluid (ELF)-to-plasma ratios using salbutamol as a reference compound. Stochastic simulation-estimation (SSE) methods were employed to assess the feasibility of different sampling strategies for estimating key parameters of the PBPK model. First, we evaluated using one or two sampling techniques within a single bronchoscopy session. Second, we compared uniform and staggered bronchosorption-based sampling strategies for drugs from different permeability categories. RESULTS: The minimal PBPK model described pulmonary PK of salbutamol across the lung and estimated the unbound tissue-plasma partition coefficient for the lung ( ) and the effective permeability ( ) of salbutamol as 11.0 and 0.543 m/h, respectively. Inter-individual variabilities (IIV) were found on plasma clearance and lung deposition fraction. No significant IIV was detected on or . Simulations indicated that low-permeability drugs exhibited higher concentrations in the ELF, while high-permeability drugs accumulated more in lung tissues, after inhalation. Results from SSE showed that bronchosorption plus biopsy were the most informative two-technique combination and bronchosorption alone was the best single-technique option. Additionally, the optimal sampling strategy for both uniform and staggered sampling depended on drug permeability, with early time points favoured for high-permeability drugs and later or broader windows needed for low-permeability drugs. CONCLUSION: A pulmonary population PBPK model for inhaled salbutamol was developed by integrating detailed intrapulmonary data from bronchoalveolar lavage, biopsy, and bronchosorption. The study revealed that parameter estimates of and were sensitive to the sampling technique. Staggered sampling strategies mitigated the risk of biased estimates, though the ideal sampling windows varied by drug's permeability. These findings support model-informed, permeability-driven study design in inhaled drug development.
Revisited Pharmacokinetic Profiles of Methylprednisolone in Plasma and Urine After Single and Multiple Oral Administrations: Relevance in Sports Drug Testing.
Coll S, Bressan C, Monfort N … +3 more , Aldea-Perona A, Carbó ML, Ventura R
Clin Pharmacokinet · 2026 Jun · PMID 42343043 · Publisher ↗
BACKGROUND: The pharmacokinetic profiles of methylprednisolone (MP) in plasma and urine were evaluated after single and multiple oral doses. MP is prohibited in sports competitions when administered systemically (oral, i...
BACKGROUND: The pharmacokinetic profiles of methylprednisolone (MP) in plasma and urine were evaluated after single and multiple oral doses. MP is prohibited in sports competitions when administered systemically (oral, injectable, or rectal administrations) whereas other routes remain permitted for therapeutic purposes. OBJECTIVE: The aim of this study was to characterize the urinary MP excretion after oral administration to assess whether the current World Anti-Doping Agency minimum reporting level of 30 ng/mL in urine is appropriate for distinguishing permitted from prohibited administrations, as well as whether the recommended washout period is adequate. Another aim was to better define MP elimination kinetics and evaluate its systemic effects. METHODS: Sixteen healthy male participants were enrolled and divided into two groups. One group received a single oral dose of 12 mg of MP, while the other received 12 mg daily for 3 consecutive days. Urine and blood samples were collected before, during, and after administration. Urine samples were analyzed for MP and 15 metabolites using a sensitive and selective liquid chromatography-tandem mass spectrometry method. Plasma samples were analyzed for unchanged MP and cortisol using liquid chromatography-tandem mass spectrometry. A pharmacokinetic analysis was performed using a one-compartment model with first-order absorption, combining plasma concentrations and urinary excretion data. RESULTS: MP represented only a small proportion of the administered dose, confirming that metabolism is the main elimination pathway. After a single oral dose, urinary MP concentrations above 30 ng/mL were observed up to 12 h, while all samples collected later were below this concentration. After multiple dosing, most samples above 30 ng/mL were also found within 12 h, although a few participants still showed concentrations above the minimum reporting level in the 12 to 24 h period. All samples collected more than 24 h after the last dose were below 30 ng/mL. In plasma, MP reached peak concentrations around 1.6-2.3 h after administration and was not detectable 24 h after the last dose. Cortisol concentrations were markedly suppressed after dosing, with recovery to baseline within 24-48 h depending on the regimen. CONCLUSIONS: This study confirms that the current urinary minimum reporting level of 30 ng/mL is appropriate for detecting oral MP use while minimizing the risk of false adverse analytical findings. The results also support the adequacy of the current 3-day washout period. Modern liquid chromatography-tandem mass spectrometry analysis and combined plasma-urine pharmacokinetic modeling provided robust evidence that MP is rapidly eliminated, extensively metabolized, and associated with transient cortisol suppression after oral administration. CLINICAL TRIAL REGISTRATION: EudraCT number 2020-004596-41.
ALBI Grade is a Determinant of Lenvatinib Pharmacokinetics, Efficacy, and Toxicities in Japanese Patients with Hepatocellular Carcinoma.
Suzuki K, Otoyama Y, Matsumoto N … +17 more , Masuo Y, Nakajima Y, Sugiura I, Fuji T, Nomura E, Ichikawa Y, Shimozuma Y, Uchikoshi M, Hayano M, Hanano M, Murase R, Mitomori C, Oka K, Sakaki M, Kato Y, Yoshida H, Fujita KI
Clin Pharmacokinet · 2026 Jun · PMID 42337221 · Publisher ↗
BACKGROUND AND OBJECTIVE: The doses of lenvatinib for patients with hepatocellular carcinoma (HCC) are determined using the Child-Pugh classification and body weight. Because lenvatinib is highly bound to plasma albumin...
BACKGROUND AND OBJECTIVE: The doses of lenvatinib for patients with hepatocellular carcinoma (HCC) are determined using the Child-Pugh classification and body weight. Because lenvatinib is highly bound to plasma albumin (98.6%), patients with low plasma albumin levels and hepatic lenvatinib clearance may exhibit a high unbound fraction and/or concentration of lenvatinib in the plasma to alter efficacy and toxicity. This study exploratorily and prospectively examined the effects of baseline albumin-bilirubin (ALBI) on systemic exposure to unbound lenvatinib and lenvatinib clinical responses in patients with HCC. PATIENTS AND METHODS: Patients with HCC who received lenvatinib were enrolled. Total- and unbound-base dose-normalized area under the plasma concentration-time curve (AUCt/dose and AUCu/dose, respectively) were determined. Progression-free survival (PFS) and toxicities were evaluated. RESULTS: Forty-one patients were enrolled between May 2020 and January 2024. AUCu/dose, but not AUCt/dose, was significantly negatively correlated with ALBI score (P = 0.00699). Patients with ALBI grade ≥ 2b had significantly higher AUCu/dose than those with < 2b (mean ± SD, 0.00602 ± 0.00268 vs. 0.00390 ± 0.00168 h/L, P = 0.0131). Child-Pugh class was associated with AUCu/dose (P = 0.0312); however, among Child-Pugh classification components, albumin only was associated with the AUCu/dose. Multivariate Cox proportional hazards analysis identified ALBI grade ≥ 2b as risk factor for shorter PFS (P = 0.0000521; hazard ratio 9.43; 95% confidence interval 3.18-28.0). ALBI grade ≥ 2b, but not Child-Pugh class, showed a significantly higher incidence of lenvatinib-induced toxicity grades ≥ 2 than ALBI grade < 2b (87.0 vs. 55.6%, P = 0.0357). CONCLUSION: The study exploratorily found that baseline ALBI grade was associated with lenvatinib AUCu/dose and clinical responses. TRIAL REGISTRATION NUMBER: UMIN000057138 (registered on February 27, 2025).
Quantitative Pharmacology Justifying Ribociclib Dose in Early Breast Cancer.
Ji Y, Wang C, Combes FP … +5 more , Ho YY, Fasching PA, Untch M, Zarate JP, Crown J
Clin Pharmacokinet · 2026 Jun · PMID 42334791 · Publisher ↗
BACKGROUND AND OBJECTIVE: Ribociclib was recently approved for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer (EBC) at the starting dose of 400 mg orally...
BACKGROUND AND OBJECTIVE: Ribociclib was recently approved for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer (EBC) at the starting dose of 400 mg orally once daily (3 weeks on/1 week off), following previous approval in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer at the starting dose of 600 mg orally once daily (3 weeks on/1 week off). This study aims to characterize ribociclib pharmacokinetics and its relationship with QT interval corrected according to Fridericia's formula (QTcF) in patients with EBC and justify the dose in EBC. METHODS: Data from several studies, including the pivotal phase III trial in patients with EBC and phase I-III trials in patients with advanced breast cancer and advanced cancer were analyzed. Ribociclib pharmacokinetics was characterized by non-compartmental or population pharmacokinetic analyses. The exposure-QTcF relationship was assessed by linear mixed-effects modeling. Neutropenia and QTcF data were compared by dose and population. RESULTS: At the 400-mg dose, ribociclib steady-state clearance was ~ 20% higher in patients with EBC than patients with advanced cancer, suggesting differences in pharmacokinetics between populations. Steady-state mean area under the plasma concentration-time curve and maximum (peak) plasma drug concentration were ~ 50% lower and steady-state clearance was ~ 50% higher in patients with EBC receiving 400 mg compared with patients with advanced cancer and advanced breast cancer receiving 600 mg, attributed to differences in both dose and population. The pharmacokinetic-QTcF analysis showed that the patient population was a significant covariate in QTcF response. The model-estimated mean change from baseline in QTcF at steady-state maximum (peak) plasma drug concentration was substantially lower in patients with EBC receiving 400 mg (10.0 ms) versus in patients with advanced breast cancer receiving 600 mg (20.7-23.7 ms), likely due to the dose and pharmacokinetic exposure effect and the population effect. Patients with EBC receiving 400 mg experienced lower rates and severity of both neutropenia and QTcF prolongation than patients with advanced breast cancer receiving 600 mg. CONCLUSIONS: This integrative analysis characterized the ribociclib pharmacokinetic and exposure-QTcF relationship, revealed the population effect on both pharmacokinetic and QTcF response, and justified the 400-mg dose in EBC. This work illustrates the utility and impact of quantitative pharmacology in justifying different doses across different patient populations for oncology therapies. CLINICAL TRIAL REGISTRATION: NATALEE (NCT03701334, 2018-09-21); AMALEE (NCT03822468, 2019-01-28); MONALEESA-2 (NCT01958021, 2013-10-04); MONALEESA-3 (NCT02422615, 2015-04-01); MONALEESA-7 (NCT02278120, 2014-10-22); X1101 (NCT01898845, 2013-07-01); X2101 (NCT01237236, 2010-11-05); X2107 (NCT01872260, 2013-05-30).
Population Pharmacokinetics of Intravenous Vitamin C in Adults with Sepsis: A Sub-study of the LOVIT Trial.
Kanji S, Hernández-Mitre MP, Blain H … +8 more , Adhikari NKJ, Lamontagne F, Battista MC, Ménard J, Sprague S, Masse MH, Roberts JA, LOVIT Investigators
Clin Pharmacokinet · 2026 Jun · PMID 42329551 · Publisher ↗
BACKGROUND AND OBJECTIVES: High-dose intravenous vitamin C was associated with increased harm in adults with sepsis requiring vasopressors in the large international LOVIT trial. This population pharmacokinetic sub-study...
BACKGROUND AND OBJECTIVES: High-dose intravenous vitamin C was associated with increased harm in adults with sepsis requiring vasopressors in the large international LOVIT trial. This population pharmacokinetic sub-study of LOVIT aimed to characterise the pharmacokinetics of vitamin C and explore associations with patient characteristics and outcomes. METHODS: Patients who enrolled in the LOVIT trial were randomized to receive 50 mg/kg vitamin C every 6 hours for 96 hours or placebo. Blood samples were collected on study Days 1, 3, and 7 for plasma vitamin C quantification. Population pharmacokinetic modeling was performed, with relevant patient and treatment-related factors tested as covariates. Internal validation was conducted using bootstrap resampling (n = 1000). Univariable and multivariable analyses explored associations between 28-day mortality and patient characteristics, as well as the relationship between vitamin C exposure and severity of illness. RESULTS: A total of 464 samples from 161 patients who were randomized to vitamin C were analysed. The median age was 64 (interquartile range [IQR] 56-72) years, weight 82 (IQR, 70-94) kg, and APACHE II score 24 (IQR, 18-29); 65.2% were male. A one-compartment model best described the data, with clearance (CL) significantly influenced by CKD-EPI eGFR and APACHE II score. Population mean estimates for clearance and volume of distribution were 3.37 L/h and 45.06 L, respectively. The model was internally validated and demonstrated to be robust and stable. Although greater vitamin C exposure was observed among non-survivors versus survivors (median 1900.5 [IQR 1191.8-2548.2] vs 1017.8 [IQR 630-1836.7] mg·h/L; p < 0.001), only age (odds ratio [OR] 1.063; 95% confidence interval [CI] 1.024-1.104, p = 0.001) and APACHE II score (OR 1.079; 95% CI 1.005-1.158, p = 0.036) were independently associated with 28-day mortality. Severity of illness was also predictive of vitamin C exposure. CONCLUSIONS: Vitamin C pharmacokinetics are highly variable between individuals. Some of this variability can be explained by changes in glomerular filtration and APACHE II score as a measure of illness severity. Although non-survivors had greater vitamin C exposure than survivors, exposure was not independently associated with mortality.
Blood Never Lies: The PopPK-Based Lie Detector.
Chaiben S, Gandia P, Duly-Bouhanick B … +2 more , Goldwirt L, Concordet D
Clin Pharmacokinet · 2026 Jun · PMID 42301614 · Publisher ↗
BACKGROUND AND OBJECTIVE: Accurate assessment of drug adherence is essential for long-term oral therapies, where self-administration is unsupervised. Conventional tools such as self-reports, electronic monitors, and even...
BACKGROUND AND OBJECTIVE: Accurate assessment of drug adherence is essential for long-term oral therapies, where self-administration is unsupervised. Conventional tools such as self-reports, electronic monitors, and even therapeutic drug monitoring often fail to detect non-adherence. Population pharmacokinetic modeling improves objectivity but typically relies on a single analyte, which may still miss hidden non-adherence. We propose a bi-analyte population pharmacokinetic-based approach that uses both the parent drug and a metabolite with distinct pharmacokinetics to enhance adherence detection and reconstruct likely dosing histories. METHODS: A literature review identified spironolactone and its metabolite canrenone as suitable candidates, based on long-term use and an available population pharmacokinetic model capturing distinct elimination profiles. Virtual patients were simulated under steady-state assumptions, then exposed to various adherence scenarios. A modified Metropolis-Hastings algorithm jointly estimated individual pharmacokinetic parameters and dosing patterns by analyzing simulated drug and metabolite concentrations. The probability of taking 0, 1, or 2 tablets per day was inferred, and a posterior adherence probability was derived from the posterior distribution to quantify adherence likelihood. A receiver operating characteristic analysis was used to evaluate diagnostic performance. RESULTS: The combined use of parent and metabolite improved non-adherence detection compared with either alone, particularly for recent missed doses. Trough concentrations outperformed peak concentrations, especially when patients did not compensate with extra doses. CONCLUSIONS: This probabilistic bi-analyte approach enhances non-adherence detection and is adaptable to other pharmacokinetic settings where distinct profiles and low model variability are present.
Elranatamab Population Pharmacokinetics and Exposure-Response for Cytokine Release Syndrome in Patients with Relapsed or Refractory Multiple Myeloma.
Hibma JE, Irby D, Liu A … +11 more , Elmeliegy M, King LE, Gifondorwa D, Jiang S, Poels KE, Soltantabar P, Lon HK, Shtylla B, Wang D, Williams JH, Nicholas T
Clin Pharmacokinet · 2026 Jun · PMID 42287565 · Publisher ↗
BACKGROUND AND OBJECTIVE: A population pharmacokinetics (PopPK) model was developed for elranatamab, a bispecific antibody targeting both B-cell maturation antigen (BCMA) and cluster of differentiation 3 (CD3), to charac...
BACKGROUND AND OBJECTIVE: A population pharmacokinetics (PopPK) model was developed for elranatamab, a bispecific antibody targeting both B-cell maturation antigen (BCMA) and cluster of differentiation 3 (CD3), to characterize the PopPK of elranatamab and guide clinical development. Elranatamab is approved in several countries for the treatment of relapsed or refractory multiple myeloma. METHODS: The PopPK model incorporated data from four clinical studies and described both free and total elranatamab as well as soluble BCMA (sBCMA) using a semi-mechanistic two-compartment target-binding model. In total there were 13,233 observations from 321 participants who received intravenous (IV) or subcutaneous (SC) elranatamab monotherapy with doses ranging from 0.1 to 1000 µg/kg. RESULTS: Elranatamab exhibited approximately linear PK over the dose range evaluated (i.e., 6-76 mg SC), with limited cellular target-mediated drug disposition and generally proportional exposure, with modest deviations at very high baseline sBCMA. None of the potential covariates evaluated, including age, sex, body weight, baseline sBCMA, and immunogenicity, were found to be clinically significant predictors of elranatamab exposure. Exposure-response analyses identified early peak exposure and tumor burden as key predictors of cytokine release syndrome (CRS), primarily after the first step-up dose. Simulations supported restarting treatment without re-priming after dose interruptions of up to 12 weeks. CONCLUSION: These findings support the approved fixed-dose regimen and provide a framework for clinical management of elranatamab in relapsed or refractory multiple myeloma. CLINICAL TRIAL REGISTRATION: NCT03269136, NCT04798586, NCT04649359, NCT05014412.
Therapeutic Drug Monitoring and Model-Informed Precision Dosing of Oral TKIs and PARP Inhibitors: A Practical Framework for Clinical Implementation.
Torrent-Rodríguez A, Bastida C, Martín ECS … +13 more , Escartín IM, Puszkiel A, Blanchet B, Laguna JC, Gorria T, Montes A, Macías I, Alvárez A, Arance A, Moreno FA, Fabregat-Bolufer AB, Soler E, Muner DS
Clin Pharmacokinet · 2026 Jun · PMID 42283932 · Full text
Oral tyrosine kinase inhibitors and poly (adenosine diphosphate-ribose) polymerase inhibitors are widely used across solid tumors and hematologic malignancies and are typically administered at fixed doses. However, subst...
Oral tyrosine kinase inhibitors and poly (adenosine diphosphate-ribose) polymerase inhibitors are widely used across solid tumors and hematologic malignancies and are typically administered at fixed doses. However, substantial interindividual pharmacokinetic variability results in heterogeneous systemic exposure, potentially leading to underexposure with reduced antitumor efficacy or overexposure with preventable toxicity. Therapeutic drug monitoring and model-informed precision dosing have emerged as complementary strategies to individualize dosing and optimize the exposure-response balance in routine oncology practice. This narrative problem-oriented review evaluates the clinical applicability of therapeutic drug monitoring and model-informed precision dosing for selected oral targeted agents, including epidermal growth factor receptor, anaplastic lymphoma kinase, BCR-ABL, vascular endothelial growth factor receptor, mitogen-activated protein kinase kinase, and multi-kinase inhibitors, as well as poly(adenosine diphosphate-ribose) polymerase inhibitors. For each agent, we assessed the presence of clinically meaningful exposure-response or exposure-toxicity relationships, the availability of validated assays, and the existence of actionable concentration thresholds. We also integrated an updated therapeutic drug monitoring usefulness score to contextualize the strength of recommendation. High-level evidence, including prospective interventional studies, supports exposure-guided dosing for imatinib and sunitinib, demonstrating improved molecular or clinical outcomes when predefined trough concentration targets are achieved. For alectinib, cabozantinib, trametinib, and lenvatinib, consistent exposure-response or exposure-toxicity relationships and pragmatic concentration thresholds support selective implementation, although randomized validation remains limited. For agents such as osimertinib, brigatinib, olaparib, and niraparib, monitoring appears most clinically relevant in toxicity-driven scenarios rather than for efficacy optimization. In contrast, lorlatinib currently lacks a clearly defined therapeutic window, limiting routine applicability. Across drugs, steady-state trough concentration remains the default sampling strategy. Clinical scenarios warranting measurement include early or unexpected disease progression, recurrent or severe adverse events, suspected drug-drug interactions, altered absorption, organ dysfunction, or concerns regarding adherence. Model-informed precision dosing extends conventional monitoring by integrating patient-specific covariates with pharmacokinetic models to simulate individualized dosing regimens. In conclusion, therapeutic drug monitoring and model-informed precision dosing are ready for selective clinical adoption in a subset of oral targeted therapies. Future prospective trials integrating pharmacometric tools with patient-centered outcomes are required to refine exposure targets and expand evidence-based implementation.
A Model-Informed Early Prediction of Methotrexate-Induced Acute Kidney Injury in Pediatric Patients with Osteosarcoma Using Real-World Data: A Multi-center Pharmacokinetic Study.
Rega P, Vallespin JM, Aldaz A … +8 more , Pappas A, Guido PC, Azocar M, Villarroel M, Pauley JL, Stewart CF, Ibarra M, Schaiquevich P
Clin Pharmacokinet · 2026 Jun · PMID 42243443 · Publisher ↗
BACKGROUND AND OBJECTIVE: High-dose methotrexate is central to pediatric osteosarcoma treatment, but delayed elimination increases the risk of acute kidney injury, compromising treatment intensity. Current therapeutic dr...
BACKGROUND AND OBJECTIVE: High-dose methotrexate is central to pediatric osteosarcoma treatment, but delayed elimination increases the risk of acute kidney injury, compromising treatment intensity. Current therapeutic drug monitoring often identifies toxicity too late for intervention. This study aimed to develop a population pharmacokinetic model using real-world data to identify early predictors of methotrexate-associated acute kidney injury. METHODS: We conducted a multicenter study including 248 pediatric, adolescent, and young adult patients with osteosarcoma (1809 high-dose methotrexate courses) from referral centers in Argentina, Chile, Spain, and the USA. A population pharmacokinetic model was developed using Monolix. Early predictors of acute kidney injury were assessed using receiver operating characteristic curve analysis, and optimal sampling times earlier than those currently used in the clinics for rescue measures were explored through simulation. RESULTS: A two-compartment population pharmacokinetic model adequately described the data up to 48 h after the start of infusion. Time-varying serum creatinine was included as a key covariate for methotrexate clearance. The alpha disposition half-life was the most accurate early predictor of moderate-to-severe acute kidney injury (area under the curve-receiver operating characteristic: 0.956 (95% confidence interval (CI) 0.914-0.998); threshold: 3.4 h (95% confidence interval 2.7-3.7), sensitivity: 0.94 [95% CI 0.81-1.0], and specificity: 0.96 [95% CI 0.73-0.99]). A two-point early sampling strategy (C4 and C8-11) precisely estimated alpha disposition half-life. CONCLUSIONS: Early identification of impaired methotrexate clearance is feasible using model-based metrics available within the first 11 h after the end of infusion by means of the alpha disposition half-life. This approach may guide supportive care offering a practical tool for model-informed precision dosing in pediatric patients with osteosarcoma.
Collecting Metabolite Pharmacokinetics in Drug-Drug Interaction Studies: A Review of Industry Practices and Data Utilization.
Dubich T, van Iersel T, Mirdamadi K … +1 more , van Hoogdalem EJ
Clin Pharmacokinet · 2026 Jun · PMID 42234077 · Publisher ↗
INTRODUCTION: Systemic exposure of a sensitive probe is considered a 'gold standard' for assessment of clinical relevance of a potential cytochrome P450 (CYP)-driven drug-drug interaction (DDI). Typically, the change in...
INTRODUCTION: Systemic exposure of a sensitive probe is considered a 'gold standard' for assessment of clinical relevance of a potential cytochrome P450 (CYP)-driven drug-drug interaction (DDI). Typically, the change in systemic exposure is judged by the area under the concentration-time curve [AUC]) of the parent, but sometimes metabolite exposure is used to further elucidate the mechanism of the DDI. METHODS: For this review, we retrieved records of clinical DDI studies conducted between September 2014 and September 2024 for commonly used CYP probes (midazolam [CYP3A4], flurbiprofen [CYP2C9], omeprazole [CYP2C19], bupropion [CYP2B6], repaglinide [CYP2C8], and dextromethorphan [CYP2D6]). We reviewed these records for reported systemic or urinary metabolite endpoints, concordance of parent and metabolite results, and utilization of metabolite data in clinical recommendations reflected in the label of the investigational medicinal product (IMP). RESULTS: Although DDI studies with probes primarily metabolized by a single pathway (i.e. midazolam, flurbiprofen, omeprazole) often included metabolite endpoints, metabolite data did not add additional sensitivity in detecting the DDI and often were not used in the label recommendations. In contrast, DDI studies with probes that are metabolized by several pathways (i.e. bupropion, repaglinide) demonstrated a higher sensitivity of metabolite-to-parent ratio to detect a DDI compared with use of the parent AUC alone. Urinary phenotyping indexes (as exemplified by dextromethorphan) are rarely collected. CONCLUSIONS: Based on these findings, we formulated criteria for deciding on the relevance of metabolite endpoints in clinical DDI studies.
Renal or Hepatic Impairment Does Not Affect Pharmacokinetics, Safety, or Tolerability of Subcutaneous Cagrilintide.
Nielsen MJF, Becker NP, Duus HHH … +6 more , Kirkeby K, Kupčová V, Lauenborg BW, Low B, Svolgaard O, Witten L
Clin Pharmacokinet · 2026 Jun · PMID 42228334 · Publisher ↗
BACKGROUND AND OBJECTIVES: Cagrilintide is a long-acting amylin agonist under development as monotherapy for weight management and as a fixed-dose combination with the glucagon-like peptide-1 receptor agonist semaglutide...
BACKGROUND AND OBJECTIVES: Cagrilintide is a long-acting amylin agonist under development as monotherapy for weight management and as a fixed-dose combination with the glucagon-like peptide-1 receptor agonist semaglutide (CagriSema) for weight management and treatment of type 2 diabetes. Two studies were conducted to assess the effects of renal or hepatic impairment on pharmacokinetics, safety and tolerability following single doses of cagrilintide. METHODS: In both studies, adult participants were categorised into four groups on the basis of renal or hepatic function (normal function and mild, moderate or severe impairment) and received a single dose of cagrilintide 0.6 or 0.9 mg, respectively. The primary endpoint was area under the cagrilintide plasma concentration curve from time zero extrapolated to infinity (AUC) from baseline (day 1) to day 36 (renal impairment study) or day 39 (hepatic impairment study). Other pharmacokinetic parameters included maximum observed cagrilintide plasma concentration (C), time to C (t) and safety. RESULTS: The renal impairment study included 33 participants (normal function, n = 14; mild impairment, n = 7; moderate impairment, n = 7; severe impairment, n = 5) and the hepatic impairment study included 32 participants (normal function, n = 14; mild impairment, n = 7; moderate impairment, n = 7; severe impairment, n = 4). In both studies, total cagrilintide exposure (AUC), C and other pharmacokinetic parameters were similar across groups with no consistent patterns observed with renal or hepatic impairment. Compared with normal renal function, the estimated ratio of the mean AUC was 1.23 (90% confidence interval [CI], 0.91-1.66) in mild impairment, 1.18 (0.87-1.59) in moderate impairment and 1.21 (0.87-1.68) in severe impairment. Compared with normal hepatic function, the estimated ratio of the mean AUC was 0.99 (0.89-1.11) in mild impairment, 1.01 (0.91-1.12) in moderate impairment and 1.11 (0.96-1.30) in severe impairment. Overall, 21 and 16 treatment-emergent adverse events (TEAEs) were reported in 11 and 9 participants in the renal and hepatic studies, respectively. In both studies, no serious TEAEs, TEAEs leading to study withdrawal or deaths were reported. No increase in number of adverse events with increasing renal or hepatic impairment was observed, and no new safety or tolerability findings with cagrilintide were identified with renal or hepatic impairment. CONCLUSIONS: In these studies, within the limitations of small sample sizes, no clinically relevant differences in cagrilintide pharmacokinetics were observed in participants with renal or hepatic impairment compared with those with normal function, suggesting that dose adjustment is not warranted for these populations. Cagrilintide was well-tolerated and there were no unexpected safety issues. TRIAL REGISTRATION: Studies are registered at ClinicalTrials.gov (NCT04209049 registered 23 December 2019 and NCT05564104 registered 3 October 2022).
Vutrisiran-Mediated Knockdown of Transthyretin in Patients with ATTR Amyloidosis.
Fontana M, Algalarrondo V, Garcia-Pavia P … +9 more , Maurer MS, Gillmore JD, Cappelli F, Kolachana K, Gao X, Jadhav S, Mehrotra N, Robbie G, Badri P
Clin Pharmacokinet · 2026 May · PMID 42201475 · Publisher ↗
BACKGROUND AND OBJECTIVE: We assessed the consistency of serum transthyretin (TTR) knockdown with the RNA interference therapeutic vutrisiran across subpopulations of patients with hereditary TTR amyloidosis (ATTR) with...
BACKGROUND AND OBJECTIVE: We assessed the consistency of serum transthyretin (TTR) knockdown with the RNA interference therapeutic vutrisiran across subpopulations of patients with hereditary TTR amyloidosis (ATTR) with polyneuropathy (ATTRv-PN) in HELIOS-A (NCT03759379) and ATTR with cardiomyopathy (ATTR-CM) in HELIOS-B (NCT04153149). METHODS: Patients received vutrisiran 25 mg subcutaneously every 3 months (Q3M). Serum TTR was measured during randomized treatment through Month 18 in HELIOS-A (post-dose/peak and pre-dose/trough sampling) and Month 30 in HELIOS-B (trough only, except Week 6). The effects of intrinsic/extrinsic factors on serum TTR knockdown from baseline were assessed. Pharmacokinetic/pharmacodynamic modeling was used to support consistency in TTR knockdown between studies. RESULTS: Observed median (95% confidence interval [CI]) serum TTR knockdown with vutrisiran was 64.2% (61.6-67.8) at Week 3 (n = 114), with steady-state trough knockdown 86.2% (84.1-92.6) (n = 118) in HELIOS-A, and 69.0% (66.0-72.0) at Week 6 (n = 294), with steady-state trough knockdown 82.5% (80.5-84.9) (n = 307) in HELIOS-B. There were no meaningful differences in serum TTR percent knockdown across subgroups defined by baseline characteristics, including age, sex, ethnicity/race, weight, TTR genotype, N-terminal pro-B-type natriuretic peptide, and serum TTR concentration (both studies), and ATTRwt/ATTRv, disease stage/severity, troponin I, and tafamidis use (HELIOS-B), or anti-drug antibodies. Model-predicted peak serum TTR knockdown in HELIOS-B was sustained and consistent with observed knockdown in HELIOS-A; predicted median (95% CI) reduction at Month 30 was 87.1% (84.8-89.4). CONCLUSIONS: Vutrisiran led to rapid, sustained, and consistent TTR knockdown in HELIOS-A and HELIOS-B, supporting fixed-dose vutrisiran 25 mg Q3M across patients with ATTRv-PN and ATTR-CM.
Population Pharmacokinetics and Pharmacodynamics of Immunoglobulins: A Systematic Review.
van der Zeeuw SL, van Tilburg SJ, Jacobs BC … +4 more , Koch BCP, Dalm VASH, Crombag MBS, Preijers T
Clin Pharmacokinet · 2026 Jun · PMID 42189499 · Full text
BACKGROUND AND OBJECTIVE: Intravenous and/or subcutaneous immunoglobulins (IVIg/SCIg) are used as immunoglobulin replacement therapy (IgRT) in primary and secondary immunodeficiencies (PID/SID) and as immunomodulatory th...
BACKGROUND AND OBJECTIVE: Intravenous and/or subcutaneous immunoglobulins (IVIg/SCIg) are used as immunoglobulin replacement therapy (IgRT) in primary and secondary immunodeficiencies (PID/SID) and as immunomodulatory therapy in immune-mediated diseases. Despite empiric immunoglobulin G (IgG) target concentrations in PID, dosing remains variable and suboptimal, particularly in immune-mediated diseases lacking clear IgG target concentrations. Population pharmacokinetic (popPK) and pharmacodynamic (PD) modelling may clarify interindividual variability and support individualised dosing. Recent developments extend beyond PID, emphasising the importance of integrated PK-PD approaches to optimise IgG therapy. This review aimed to provide a comprehensive overview of popPK(-PD) models describing polyclonal IgG therapy, and to emphasise the added value of PK-PD in understanding drug behaviour. METHODS: A systematic literature search was conducted in Embase, MEDLINE, and Web of Science from inception to August 2025. Studies describing popPK(-PD) models for exogenous polyclonal IVIg and/or SCIg administration in humans were included. RESULTS: In total, 14 studies were included. While most popPK models focus on PID (N = 10), an increasing number address immune-mediated diseases. Immunoglobulin G pharmacokinetics are typically described using two-compartment models with first-order kinetics, using body weight (BW) as a common covariate for clearance and volume of distribution. Endogenous IgG is often incorporated as a fixed PK parameter; however, this may not adequately capture interindividual variability and potential effects of Ig treatment on IgG concentrations. Two popPK-PD models link IgG concentrations to clinical outcomes in immune-mediated diseases. In contrast, such models are currently lacking for PID. Simulations showed consistent predicted IgG concentrations following SCIg in PID, while IVIg models in PID showed more variability. CONCLUSIONS: PopPK models have advanced understanding of IgG PK and its variability between patients and treatment regimens. These models provide a powerful framework to support individualised dosing strategies, thereby potentially reducing reliance on empirical, trial-and-error dosing approaches. However, clear target concentrations are lacking and must be established for individual patients. Models may be further optimised by incorporating essential Neonatal Fc receptor (FcRn) mechanisms using physiology-based pharmacokinetic (PBPK) or semi-mechanistic models. In conclusion, current models are useful to predict IgG concentrations across diseases during Ig treatment; however, a clearer relationship with PD is required. Hence, these findings can guide clinical trial design for tailored dosing regimens.
Population Pharmacokinetic Analysis of Glecaprevir and Pibrentasvir in Pediatric Patients ≥ 3 to < 18 Years of Age with Genotypes 1-6 Chronic Hepatitis C Virus (HCV) Infection.
Thakre N, Beck D, Saeed AM … +6 more , Eckert D, Chen MJ, Liu W, Lon HK, Mostafa NM, Mensing S
Clin Pharmacokinet · 2026 May · PMID 42189498 · Publisher ↗
BACKGROUND: Mavyret, a combination medication of glecaprevir (GLE) and pibrentasvir (PIB), is approved to treat chronic and acute hepatitis C virus (HCV) (genotypes 1-6) infection in adults and pediatric patients ≥ 3 yea...
BACKGROUND: Mavyret, a combination medication of glecaprevir (GLE) and pibrentasvir (PIB), is approved to treat chronic and acute hepatitis C virus (HCV) (genotypes 1-6) infection in adults and pediatric patients ≥ 3 years old. To support approval, a two-part clinical trial was conducted in adolescents (≥ 12 to < 18 years) and children (≥ 3 to < 12 years) to identify the appropriate dosage and determine the efficacy and safety in pediatric patients. OBJECTIVES: Population pharmacokinetic (popPK) analyses reported herein aimed to (1) characterize the pharmacokinetic (PK) parameters of orally administered GLE and PIB and the sources of PK variability in pediatric patients and (2) support the use of a body weight-based pediatric GLE/PIB dose ratio of 50/20 mg in HCV-infected children. METHODS: PopPK models were built for GLE and PIB independently using nonlinear mixed-effects modeling and utilized data collected from 126 pediatric patients. Demographic, pathophysiological, and treatment factors were investigated for their impact on GLE and PIB PK. RESULTS: PopPK analyses of pediatric exposures confirmed comparable exposures to those of adults who achieved over 95% sustained virologic response (SVR12). The pediatric popPK model incorporated allometric body weight-based scaling and subsequently identified no covariate that significantly impacted GLE exposures. Similarly, no covariate beyond the specified allometric body weight scaling was identified to impact PIB exposures. The developed pediatric popPK models were able to describe the central tendency and variability of the data. CONCLUSION: These results supported the approval of body weight-based dosing regimens of GLE and PIB in children (< 45 kg) infected with any HCV genotype. CLINICAL TRIALS: NCT03067129.
Impact of Preclinical Verification in Physiologically Based Pharmacokinetic Modelling for First-in-Human Predictions: Application of a Published Model Building Strategy for Five Compounds.
Jackson C, Graves RH, Tran TT … +1 more , Miller NA
Clin Pharmacokinet · 2026 May · PMID 42171970 · Publisher ↗
BACKGROUND AND OBJECTIVE: Physiologically based pharmacokinetic modelling is routinely used in the pharmaceutical industry and has an impact on drug labels. New applications have emerged, one of which is first-in-human p...
BACKGROUND AND OBJECTIVE: Physiologically based pharmacokinetic modelling is routinely used in the pharmaceutical industry and has an impact on drug labels. New applications have emerged, one of which is first-in-human pharmacokinetic predictions. Scientists in this field often believe that verification of models in preclinical species is essential for accurate predictions, but consensus has not been reached and animal use across the industry deserves continual examination with the aim to reduce use. METHODS: A published model-building strategy was used to assess the accuracy added by preclinical verification for human PK prediction. Three sequential approaches were explored using five compounds covering a range of physicochemical properties and chemical classes. Approach 1 (QSPR FIH prediction), uses parameter inputs predicted using in silico Quantitative Structure Property Relationship models; Approach 2 (In vitro FIH prediction), supplements predicted parameters with in vitro measurements where available data exist; Approach 3 (Verified FIH prediction), uses preclinical in vivo pharmacokinetic data to verify the in vitro measurements. RESULTS: Preclinical verification models were able to provide predictions of first-in-human pharmacokinetics within two-fold of the observed data for all five compounds studied, which was a significant improvement compared with predictions using in silico or in vitro inputs without verification in preclinical species. In most cases, the predictions generated purely from structure were superior to those supplemented with in vitro data without preclinical validation. Prediction of human clearance via in vitro in vivo extrapolation proved challenging and was identified as the most common cause of poor predictions of human PK from in vitro data. CONCLUSIONS: The work here supports the continued considered use of preclinical verification in PBPK modelling.
Advancing Precision Dosing of 5-FU: Population PK Model Development, Limited Sampling Strategies, and Fit-for-Use Application.
Tan Z, Sancho-Araiz A, Völler S … +8 more , Peeters SLJ, Manten T, Deenen MJ, Maring JG, Bet PM, Mathôt RAA, Knibbe CAJ, Moes DJAR
Clin Pharmacokinet · 2026 May · PMID 42168702 · Publisher ↗
BACKGROUND: A significant proportion of patients receiving 5-fluorouracil-based chemotherapy have been reported to experience grade ≥ 3 toxicities, which range from 21 to 76% depending on the treatment regimen. This may...
BACKGROUND: A significant proportion of patients receiving 5-fluorouracil-based chemotherapy have been reported to experience grade ≥ 3 toxicities, which range from 21 to 76% depending on the treatment regimen. This may in part be due to interpatient variability in pharmacokinetics. More recently, only about 20% of the patients were reported to achieve the target area under the concentration-time curve from time zero to infinity of 20-30 mg*h/L. OBJECTIVE: We aimed to evaluate existing population pharmacokinetic models and develop a final pharmacokinetic model. In addition, we aimed to identify optimal limited sampling strategies to accurately estimate individual area under the concentration-time curve from time zero to infinity, facilitating model-informed precision dosing using a fit-for-use application. METHODS: Patient data from four prospective clinical studies were obtained. Published 5-fluorouracil population pharmacokinetic models were evaluated. A final model was developed, and limited sampling strategies were identified. A user-friendly model-informed precision dosing application was created for initial and subsequent dose adjustments. RESULTS: Using the published models, population predictions resulted in underestimation of observed concentrations and misspecification of a 24-h infusion regimen were observed, with the two-compartment Michaelis-Menten model outperforming the other model structures. Of this model, the parameters were re-estimated and covariates analysis was conducted. Body surface area significantly influenced the maximum rate of reaction and was implemented using allometric scaling with an exponent of 1.14 (relative standard error 24%). For a bolus in combination with a 46-h continuous infusion, the best limited sampling strategy was T = 0.1 (end of bolus), 1 and 3 h after treatment initiation; while for the 46-h continuous infusion, the optimal limited sampling strategy was T = 0.8, 2, and 5 h. Model-informed precision dosing algorithms were implemented in an model-informed precision dosing application. CONCLUSIONS: The external evaluation of 5-fluorouracil population pharmacokinetic models against a pooled prospective population resulted in a generic two-compartment Michaelis-Menten pharmacokinetic model with body surface area as a covariate on the maximum rate of reaction. The limited sampling strategy and the shiny model-informed precision dosing application demonstrated the potential for accurate dose individualization of 5-fluorouracil.
Correction: Model‑Based Alternative Dosing Strategies for Subcutaneous Nivolumab to Improve Cost Effectiveness.
Wang Y, Bukkems LH, Ter Heine R … +13 more , van Hasselt JGC, Koolen SLW, Hendrikx JJMA, Van der Hulle T, Kapiteijn E, Zwaveling J, Becker A, van den Heuvel MM, Theelen WSME, Oude Munnink TH, Smit EF, Guchelaar HJ, Moes DJAR
Clin Pharmacokinet · 2026 May · PMID 42154177 · Publisher ↗
Abstract loading — click title to view on PubMed.
Therapeutic Drug Monitoring of Imatinib in Paediatric Chronic Myeloid Leukaemia: Towards Practical Implementation and Interpretation of Measured Plasma Concentrations.
Lensker P, Gottschalk A, Zerjatke T … +7 more , Roeder I, Fromm MF, Dörje F, Suttorp M, Rauh M, Glauche I, Metzler M
Clin Pharmacokinet · 2026 May · PMID 42154176 · Publisher ↗
BACKGROUND AND INTRODUCTION: Imatinib (IMA) revolutionised the treatment of chronic myeloid leukaemia (CML). Therapeutic drug monitoring (TDM) of IMA is recommended to improve treatment outcomes in adults, but guidance f...
BACKGROUND AND INTRODUCTION: Imatinib (IMA) revolutionised the treatment of chronic myeloid leukaemia (CML). Therapeutic drug monitoring (TDM) of IMA is recommended to improve treatment outcomes in adults, but guidance for reliable interpretation of plasma concentrations in children is limited. Using real-world paediatric data, we aimed to develop a practical algorithm with recommendations for an IMA TDM procedure in paediatric oncology. METHODS: Imatinib plasma concentrations and clinical data were collected from patients enrolled in the multicentre CML-PAED-II study and subsequent registry. We evaluated the method of exponential extrapolation for estimating interpretable IMA trough concentrations and used linear mixed effects models to assess plasma concentration predictors. Associations between IMA trough concentrations and molecular response were analysed, and a paediatric-specific target threshold was evaluated. Findings were integrated into an algorithm for clinical application of IMA TDM. RESULTS: In total, 269 IMA trough concentrations from 72 patients and BCR::ABL1/ABL1 transcript ratios from 50 patients were included. Using a correction tool, we obtained estimates of trough concentration by exponential extrapolation. Administered IMA dose was the main predictor of plasma concentrations. Higher trough concentrations tended to correlate with faster initial molecular response. The adult-derived target threshold of 1000 ng/mL proved applicable in paediatric practice. The developed algorithm outlines clinical decision points and consequences, which are key elements of existing intensified clinical pharmacological/pharmaceutical care programmes during oral antitumour therapy. CONCLUSION: The algorithm supports the use of TDM during paediatric IMA treatment, enabling early identification of exposure below the targeted concentration and variations in treatment efficacy to further improve treatment outcomes.
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