Clinical Pharmacokinetics[JOURNAL]
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200 papers
Population Pharmacokinetics of Efsubaglutide Alfa in Healthy Subjects and Subjects with Type 2 Diabetes.
Lou YR, Xu YL, Xiong Y … +2 more , Deng C, Wang Q
Clin Pharmacokinet · 2025 Apr · PMID 39961992 · Publisher ↗
BACKGROUND AND OBJECTIVES: Efsubaglutide alfa is a novel long-acting human glucagon-like peptide-1 receptor agonist. Clinical studies in patients with type 2 diabetes (T2D) have shown excellent glucose-lowering effects....
BACKGROUND AND OBJECTIVES: Efsubaglutide alfa is a novel long-acting human glucagon-like peptide-1 receptor agonist. Clinical studies in patients with type 2 diabetes (T2D) have shown excellent glucose-lowering effects. This study aims to develop a population pharmacokinetic (popPK) model for efsubaglutide alfa to characterize its pharmacokinetic (PK) profile and assess the impact of intrinsic and extrinsic factors. METHODS: A popPK model was developed using a nonlinear mixed-effects model (NONMEM) based on 4173 plasma concentration measurements of efsubaglutide alfa from 911 participants, including 36 healthy subjects and 875 patients with T2D, across four clinical trials. These trials involved once-weekly subcutaneous injections of efsubaglutide alfa at doses ranging from 0.375 mg to 9.0 mg, with treatment durations spanning from 1 to 24 weeks. Diagnostic plots, visual predictive checks, nonparametric bootstrap methods, and simulations were employed to validate the model's robustness and performance. Covariates were identified using stepwise covariate modeling. RESULTS: A two-compartment model with first-order absorption and first-order elimination adequately described the PK characteristics of efsubaglutide alfa. Efsubaglutide alfa exhibited favorable absorption (K = 0.0255 per hour) and a relatively large apparent volume of distribution (V/F of 14.5 L with relative standard error [RSE] of 3%; V/F of 3.01 L). It showed moderate clearance (CL/F of 0.0680 L/h, RSE of 1%, inter-individual variability of 16.6%) and an extended half-life. In subjects with T2D, the geometric mean half-life was estimated between 182 and 215 h across the 1-3 mg dose range, supporting once-weekly or once-every-two-week dosing. Efsubaglutide alfa exposure increased proportionally with dose and remained consistent across studies. Baseline body weight (WT), baseline estimated glomerular filtration rate (eGFR), neutralizing antidrug antibody (Nab), STUDY, and planned dose (ARM) were identified as significant covariates for CL/F, while baseline WT and STUDY influenced V/F. Although baseline WT and eGFR affected exposure parameters (AUC, C, and C), these effects were not clinically significant, suggesting no need for dose adjustment. CONCLUSIONS: The final popPK model, incorporating significant covariates (baseline WT, baseline eGFR, Nab, STUDY, and ARM), provided robust and precise PK parameter estimates, confirming its applicability in both healthy subjects and those with T2D. The minimal and clinically insignificant impact of baseline WT and eGFR on drug exposure supports the conclusion that no dose adjustment is necessary based on these factors. Moreover, the higher absorption rate constant suggests a rapid onset of action, and the extended half-life supports less frequent dosing, potentially improving patient adherence. TRIAL REGISTRATION: The trials were registered at Clinicaltrials.gov (identifiers: NCT03745885, NCT04314622, NCT04994288, and NCT04998032).
Plasma Concentrations of Direct Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation and Different Degrees of Obesity.
Menichelli D, Pannunzio A, Baldacci E … +9 more , Cammisotto V, Castellani V, Mormile R, Palumbo IM, Chistolini A, Violi F, Harenberg J, Pastori D, Pignatelli P
Clin Pharmacokinet · 2025 Mar · PMID 39937335 · Full text
BACKGROUND: Atrial fibrillation (AF) has multiple cardio-metabolic comorbidities, including obesity. The use of direct oral anticoagulants (DOACs) in patients with AF and obesity is still uncertain owing to the concern o...
BACKGROUND: Atrial fibrillation (AF) has multiple cardio-metabolic comorbidities, including obesity. The use of direct oral anticoagulants (DOACs) in patients with AF and obesity is still uncertain owing to the concern of possible ineffective DOAC plasma concentration. We evaluated the peak and trough plasma concentrations of DOACs in AF patients with different degrees of obesity. METHODS: Observational single-center study including patients with obesity and AF, between April 2022 and April 2024. Obesity was defined as body mass index (BMI) ≥ 30.0 kg/m. The 2-hour peak and trough DOAC plasma concentrations were assessed. Intake of DOAC was verified on site. Multivariable logistic regression analysis was used to assess the odds ratio (OR) and 95% confidence interval (95% CI) of factors associated with below-range trough concentration (BRTC) and below-range peak concentration (BRPC). RESULTS: In total, 160 patients (33.8% women) with a mean age of 73.2 ± 9.1 years were included. The median BMI was 32.3 kg/m. DOACs prescribed were apixaban (46.8%), rivaroxaban (21.8%), dabigatran (16.4%), and edoxaban (15.0%); 18.1% and 14.4% had BRTC and BRPC concentrations, respectively. Patients with BRTC were more frequently treated with edoxaban and dabigatran and had a higher BMI. On multivariable logistic regression analysis, dabigatran [hazard ratio (HR) 3.039, 95% CI 1.155-7.999, p = 0.024) and BMI ≥ II class (OR 2.625, 95% CI 1.087-6.335, p = 0.032] were associated with BRTC. Dabigatran (OR 4.296, 95% CI 1.523-12.120, p = 0.006) and apixaban (OR 0.277, 95% CI 0.096-0.802, p = 0.018) were directly and inversely associated with BRPC, respectively. CONCLUSIONS: A nonnegligible proportion of patients with obesity and AF have below-range plasma concentrations of DOACs. Assessment of DOAC plasma concentration in obesity class ≥ II may be useful in these patients.
Clinical Exploration and Physiologically Based Modelling of the Impact of Hepatic Impairment on Entrectinib Pharmacokinetics.
Ozbey AC, Meneses-Lorente G, Simmons B … +4 more , McCallum S, Annaert P, Parrott N, Umehara K
Clin Pharmacokinet · 2025 Mar · PMID 39934586 · Publisher ↗
BACKGROUND AND OBJECTIVES: This study investigates the pharmacokinetics (PK) of entrectinib and its metabolite M5 (CYP3A4 substrates) in patients with hepatic impairment (HI) and applies physiologically based pharmacokin...
BACKGROUND AND OBJECTIVES: This study investigates the pharmacokinetics (PK) of entrectinib and its metabolite M5 (CYP3A4 substrates) in patients with hepatic impairment (HI) and applies physiologically based pharmacokinetic (PBPK) modelling to understand the observed changes mechanistically. METHOD: After a single oral administration of entrectinib at 100 mg, measured plasma concentrations for entrectinib and M5 in control subjects and HI patients were compared to predictions made with Simcyp. Model sensitivity analyses explored the possible reasons for mismatches to observed data. Reduced oral absorption due to lower bile salt (BS) levels in the intestinal lumen in hepatic impairment was examined. RESULTS: Physiologically based pharmacokinetic model simulations overestimated the 80% increase in entrectinib area under the plasma concentration curve between 0h to infinity (AUC) observed in patients with severe HI, predicting a > 2-fold rise. Observed maximal plasma concentration (C) increased by 25% from controls to mild HI but decreased by 61% from mild to severe HI. Although the model predicted C within a 2-fold range, there was a trend to greater over-prediction with increasing HI severity. For M5, PBPK modelling did not capture the observed trends well. The C and AUC were overestimated in HI patients and the trend to reduction of C with minimal change in AUC with increasing severity of HI was not well captured. Decreasing Simcyp default luminal BS concentrations by 2-, 6-, and 8.7-fold for mild, moderate, and severe HI improved the predictions for both entrectinib and M5. CONCLUSION: Physiologically based pharmacokinetic model simulations tended to overestimate the observed moderate changes in entrectinib exposures due to HI. For improved prediction of poorly soluble lipophilic drugs like entrectinib there is a need for PBPK models of HI to account for additional pathophysiological changes such as reduced intestinal BS levels. TRIAL REGISTRATION: NCT number: NCT04226833.
Population Pharmacokinetics of Cobicistat and its Effect on the Pharmacokinetics of the Anticancer Drug Olaparib.
Overbeek JK, van Erp NP, Burger DM … +4 more , den Broeder AA, Koolen SLW, Huitema ADR, Ter Heine R
Clin Pharmacokinet · 2025 Mar · PMID 39909979 · Full text
OBJECTIVES: Pharmacokinetic (PK) boosting is the intentional use of strong inhibitors of metabolic enzymes or transporters to boost the systemic exposure of a therapeutic drug. PK boosting is expanding to therapeutic are...
OBJECTIVES: Pharmacokinetic (PK) boosting is the intentional use of strong inhibitors of metabolic enzymes or transporters to boost the systemic exposure of a therapeutic drug. PK boosting is expanding to therapeutic areas outside human immunodeficiency virus (HIV) therapy. Data on the PK of the booster cobicistat and its effect on CYP3A-substrates outside of HIV therapy are lacking. This study aimed to describe the PK of once- and twice-daily cobicistat regimens in healthy volunteers and patients with rheumatoid arthritis, cancer, or HIV infection and to investigate the interplay between cobicistat and the anticancer drug olaparib. METHODS: Cobicistat levels from 683 samples from 66 subjects in four clinical trials were included in the analysis. For olaparib, 261 samples from 12 subjects from one trial were included. Population PK analysis was performed by nonlinear mixed-effects modelling. RESULTS: Both cobicistat and olaparib PK were adequately described by a well-stirred liver model with one central compartment and Erlang type absorption. Cobicistat PK was similar across patient populations and dosing regimens. Cobicistat increased olaparib prehepatic bioavailability 1.65-fold (RSE 6%) and decreased intrinsic clearance 0.34-fold (RSE 6.5%). A correlation between olaparib PK and cobicistat exposure could not be identified. The interindividual variability in olaparib clearance was lower with cobicistat than without cobicistat. CONCLUSIONS: The developed pharmacokinetic models adequately described cobicistat and olaparib plasma concentrations. PK boosting with cobicistat at 150 mg twice daily led to an increase in olaparib bioavailability and decrease in clearance. This effect was not correlated with cobicistat exposure, which may reflect saturation of the boosting effect of cobicistat at this dose. TRIAL REGISTRATION NUMBERS (DATE OF REGISTRATION): NCT02565888 (30-09-2015), NCT00825929 (19-01-2009), Netherlands Trial Register NL7766 (18-12-2018), NCT05078671 (22-09-2021).
Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a 2-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer's Disease.
Hey JA, Yu JY, Abushakra S … +5 more , Schaefer JF, Power A, Kesslak P, Paul J, Tolar M
Clin Pharmacokinet · 2025 Mar · PMID 39907966 · Full text
INTRODUCTION: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of β-amyloid (Aβ) oligomer formation in late-stage development as a potential disease-modifying therapy for Alzheimer's disease (AD). ALZ-801,...
INTRODUCTION: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of β-amyloid (Aβ) oligomer formation in late-stage development as a potential disease-modifying therapy for Alzheimer's disease (AD). ALZ-801, a valine-conjugated prodrug, is rapidly converted to tramiprosate after oral dosing. Upon conversion to tramiprosate, it generates a single metabolite, 3-sulfopropanoic acid (3-SPA). Both tramiprosate and 3-SPA are active anti-Aβ oligomer agents that mediate ALZ-801's central mechanism of action (MOA). We summarize herein the pharmacokinetics (PK) of ALZ-801 in apolipoprotein ε4 (APOE4) carrier subjects with early AD from a phase 2 trial. METHODS: The ALZ-801 phase 2 study was designed to evaluate longitudinal effects of ALZ-801 (265 mg BID) on plasma, cerebrospinal fluid (CSF) and volumetric magnetic resonance imaging (MRI) AD biomarkers, and clinical outcomes over 104 weeks in APOE4 carriers with early AD. Eighty-four subjects (31 APOE4/4 homozygotes and 53 APOE3/4 heterozygotes) with positive CSF biomarkers of amyloid and tau pathology were enrolled. The phase 2 study included a substudy of 24 subjects to provide 8-h steady-state PK at 65 weeks. Sparse PK samples were also analyzed. The relationships between plasma PK exposure and clinical characteristics [i.e., sex, APOE genotype, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), concomitant acetylcholinesterase inhibitor (AChEI) use, and tablet lot] were evaluated. RESULTS: The steady-state plasma PK results were closely aligned with the previous 2-week PK in the ALZ-801 phase 1b study in APOE4 carrier subjects with AD, as well as a phase 1 7-day PK study in heathy elderly volunteers. Following oral dosing, ALZ-801 was rapidly converted to the active moieties, tramiprosate and 3-SPA. The intersubject variability in plasma drug levels was low, confirming the superior performance of ALZ-801 versus oral tramiprosate tablet (150 mg BID) from the earlier tramiprosate phase 3 trials. Correlation analysis versus clinical characteristics showed that plasma exposures (Cmax and AUC8h) for ALZ-801, tramiprosate, and 3-SPA were not affected by sex, APOE genotype, age, BMI, concomitant AChEI use, or tablet lot. Plasma exposures of both tramiprosate and 3-SPA, but not ALZ-801, were inversely correlated with eGFR, in line with renal excretion as the primary route of elimination. ALZ-801 was well tolerated without new safety signals or events of amyloid-related imaging abnormalities (ARIA). CONCLUSIONS: The steady-state PK profile of oral ALZ-801 in subjects with early AD was not affected by sex, APOE genotype, age, BMI, concomitant use of AChEI, or tablet lot. The inverse relationship of plasma exposures of tramiprosate and 3-SPA, but not ALZ-801, versus eGFR is consistent with renal clearance as the primary route of elimination for tramiprosate and 3-SPA (active moieties), and with the efficient conversion of ALZ-801 prodrug to the active moieties after dosing. These results demonstrate that ALZ-801 displays favorable PK properties without evidence of interactions with demographic characteristics and support its development as an oral disease-modifying treatment for AD. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04693520 .
Effect of Hepatic Impairment or Renal Impairment on the Pharmacokinetics of Aficamten.
Xu D, Lutz JD, Divanji P … +6 more , Li J, Benattia Y, Griffith A, Heitner SB, Kupfer S, German P
Clin Pharmacokinet · 2025 Mar · PMID 39907965 · Full text
BACKGROUND AND OBJECTIVE: Aficamten, a small-molecule, selective cardiac myosin inhibitor, is under development for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Aficamten is primarily elim...
BACKGROUND AND OBJECTIVE: Aficamten, a small-molecule, selective cardiac myosin inhibitor, is under development for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Aficamten is primarily eliminated by hepatic metabolism with renal excretion playing a minor role. The objective of this investigation was to evaluate the pharmacokinetics (PK) of aficamten in moderate hepatic impairment or mild to moderate renal impairment to inform dosing recommendations in HCM patients with mild or moderate hepatic impairment or mild to moderate renal impairment. METHODS: The impact of hepatic impairment on the PK of single-dose aficamten 20 mg was evaluated in a phase 1 single-dose, open-label, parallel-group study, in healthy participants with moderate (n = 8) hepatic impairment (Child-Pugh B classification) versus participants with normal hepatic function (n = 8). Safety was monitored throughout. The effect of renal impairment on aficamten PK was assessed using population PK (PopPK) modelling of phase 2/3 clinical data in patients with oHCM. RESULTS: Aficamten PK was similar in participants with moderate hepatic impairment and those with normal hepatic function. No serious or severe treatment-emergent adverse events or clinically significant laboratory abnormalities were reported. There were no clinical meaningful differences in aficamten exposure in patients with oHCM with mild or moderate renal impairment and those with normal renal function. CONCLUSIONS: No clinically relevant changes in aficamten PK were observed in participants with moderate hepatic impairment. Population PK analysis indicated mild or moderate renal impairment and had no statistically or clinically significant impact on aficamten PK in patients with oHCM. Aficamten dose adjustment may not be necessary in patients with mild or moderate hepatic or renal impairment.
Solubility-Limited Absorption Identified by a Simplified PBPK Model for the Prediction of Positive Food Effect for BCS II/IV Drugs.
Rodriguez-Fernandez K, Gómez-Mantilla JD, Shukla S … +2 more , Mangas-Sanjuán V, Peters SA
Clin Pharmacokinet · 2025 Mar · PMID 39899202 · Publisher ↗
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Evaluation of Solubility-Limited Absorption as a Surrogate to Predicting Positive Food Effect of BCS II/IV Drugs.
Rodriguez-Fernandez K, Gómez-Mantilla JD, Shukla S … +4 more , Stopfer P, Sieger P, Mangas-Sanjuán V, Peters SA
Clin Pharmacokinet · 2025 Mar · PMID 39899201 · Full text
INTRODUCTION AND OBJECTIVE: Physiologically based pharmacokinetic (PBPK) models are increasingly used to predict food effect (FE) but model parameterization is challenged by in vitro-in vivo (IVIV) disconnect and/or para...
INTRODUCTION AND OBJECTIVE: Physiologically based pharmacokinetic (PBPK) models are increasingly used to predict food effect (FE) but model parameterization is challenged by in vitro-in vivo (IVIV) disconnect and/or parameter nonidentifiability. To overcome these issues, we propose a simplified PBPK model, in which all solubility-driven processes are lumped into a single parameter, solubility, which is optimized against observed concentration-time data. METHODS: A set of commercially available biopharmaceutical classification system (BCS) II/IV compounds was selected to measure the solubility in a fasted state simulated intestinal fluid (FaSSIF) medium. The compounds were ranked from the lowest to the highest dose-adjusted FaSSIF solubility (FaSSIF/D) value and subdivided into three areas based on an upper and a lower limit: drugs with FaSSIF/D > upper limit having no FE, drugs with FaSSIF/D < lower limit having FE, and drugs between the limits said to be in the sensitivity range (SR), for which we tested the hypothesis that solubility-limited absorption (SLA) identified by simplified PBPK model can reliably predict positive FE if their exposures are not impacted by gut efflux or gut metabolism. RESULTS: We demonstrate, using a subset of drugs within SR for which PBPK models were available, that drugs with SLA exhibited a positive FE, while those with no SLA did not show FE. CONCLUSIONS: This proposal allows for a reliable binary prediction of FE to enable timely decisions on the need for pilot FE studies as well as the timing of pivotal FE studies.
Exposure to Rifampicin and its Metabolite 25-Deacetylrifampicin Rapidly Decreases During Tuberculosis Therapy.
Goutelle S, Bahuaud O, Genestet C … +5 more , Millet A, Parant F, Dumitrescu O, Ader F, Lyon TB Study Group
Clin Pharmacokinet · 2025 Mar · PMID 39871048 · Full text
BACKGROUND AND OBJECTIVE: Limited information is available on the pharmacokinetics of rifampicin (RIF) along with that of its active metabolite, 25-deacetylrifampicin (25-dRIF). This study aimed to analyse the pharmacoki...
BACKGROUND AND OBJECTIVE: Limited information is available on the pharmacokinetics of rifampicin (RIF) along with that of its active metabolite, 25-deacetylrifampicin (25-dRIF). This study aimed to analyse the pharmacokinetic data of RIF and 25-dRIF collected in adult patients treated for tuberculosis. METHODS: In adult patients receiving 10 mg/kg of RIF as part of a standard regimen for drug-susceptible pulmonary tuberculosis enrolled in the Opti-4TB study, plasma RIF and 25-dRIF concentrations were measured at various occasions. The RIF and 25-dRIF concentrations were modelled simultaneously by using a population approach. The area under the concentration-time curves of RIF and 25-dRIF were estimated on each occasion of therapeutic drug monitoring. Optimal RIF exposure, defined as an area under the concentration-time curve over 24 hours/minimum inhibitory concentration > 435, was assessed. RESULTS: Concentration data (247 and 243 concentrations of RIF and 25-dRIF, respectively) were obtained in 35 patients with tuberculosis (10 women, 25 men). Mycobacterium tuberculosis minimum inhibitory concentration ranged from 0.06 to 0.5 mg/L (median = 0.25 mg/L). The final model was a two-compartment model including RIF metabolism into 25-dRIF and auto-induction. Exposure to 25-dRIF was low, with a mean area under the concentration-time curve over 24 h ratio of 25-dRIF/RIF of 14 ± 6%. The area under the concentration-time curve over 24 h of RIF and 25-dRIF rapidly decreased during therapy, with an auto-induction half-life of 1.6 days. Optimal RIF exposure was achieved in only six (19.3%) out of 31 patients upon first therapeutic drug monitoring. CONCLUSIONS: Exposure to both RIF and 25-dRIF rapidly decreased during tuberculosis therapy. The contribution of 25-dRIF to overall drug exposure was low. Attainment of the target area under the concentration-time curve over 24 hours/minimum inhibitory concentration for RIF was poor, supporting an increased RIF dosage as an option to compensate for auto-induction.
Population Pharmacokinetic Modelling of Apixaban in End-Stage Kidney Disease Patients with Atrial Fibrillation Receiving Haemodialysis.
Konecki C, Lipman ML, Mavrakanas TA … +1 more , Djerada Z
Clin Pharmacokinet · 2025 Feb · PMID 39853633 · Publisher ↗
BACKGROUND AND OBJECTIVE: Apixaban is increasingly being used for stroke prevention in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis, but no pharmacostatistical model is availab...
BACKGROUND AND OBJECTIVE: Apixaban is increasingly being used for stroke prevention in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis, but no pharmacostatistical model is available for dosage adjustment. This study aimed to develop a population pharmacokinetic model of apixaban in these patients to characterise its dialytic clearance and determine optimal dosing regimens and discontinuation timing before surgery. METHODS: Patients received 2.5 mg of apixaban twice daily for 9 days, followed by 5 mg twice daily for 8 days after a 5-day washout period (NCT02672709). Apixaban concentrations were measured on and off dialysis. A population pharmacokinetic model was developed using parametric and non-parametric methods. Simulations were performed to assess plasmatic exposure and the time to reach clinically relevant apixaban concentrations after treatment discontinuation for seven dosing regimens and 13 dialysis schedules. RESULTS: A total of 289 apixaban concentrations were measured, including 85 during haemodialysis. The best model was a two-compartment model with first-order elimination. Dialytic clearance was estimated at 1.20 L/h with high inter-individual variability. Apixaban daily exposure was proportional to the total daily dose, independent of dosing frequency and dialysis timing. The standard discontinuation period of 48-72 h before surgery was insufficient to achieve clinically negligible concentrations in patients undergoing haemodialysis. CONCLUSIONS: We propose the first pharmacokinetic model to characterise apixaban clearance in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis. Simulations suggest that dialysis timing is not critical for monitoring apixaban, and the discontinuation period before surgery should be extended beyond current recommendations.
Clinical Pharmacokinetics of N,N-Dimethyltryptamine (DMT): A Systematic Review and Post-hoc Analysis.
van der Heijden KV, Otto ME, Schoones JW … +5 more , van Esdonk MJ, Borghans LGJM, van Hasselt JGC, van Gerven JMA, Jacobs G
Clin Pharmacokinet · 2025 Feb · PMID 39838235 · Full text
BACKGROUND AND OBJECTIVE: N,N-Dimethyltryptamine (DMT) is currently being studied for its therapeutic potential in various psychiatric disorders. An understanding of its pharmacokinetics (PK) is essential to determine ap...
BACKGROUND AND OBJECTIVE: N,N-Dimethyltryptamine (DMT) is currently being studied for its therapeutic potential in various psychiatric disorders. An understanding of its pharmacokinetics (PK) is essential to determine appropriate dose ranges in future clinical studies. We conducted a systematic literature review on the PK of DMT. METHODS: Clinical studies that administered known amounts of DMT and reported PK data and/or parameters in humans were included. Additionally, raw PK data were requested from authors and/or extracted from publications. RESULTS: In total, 219 references were retrieved, of which 13 publications were included, covering eight distinct datasets. All studies administered DMT intravenously in various infusion schemes, except for one intramuscular administration. High variability in dose-normalized exposure parameters and differences in exposure for bolus versus infusion administration were observed. DMT is extensively redistributed to other tissues, based on its biphasic elimination profile and high volume of distribution in the terminal elimination phase (range 123-1084 L). It is eliminated rapidly, with a half-life of 4.8-19.0 min and clearance of 8.1-46.8 L/min. This is a result of the rapid metabolization of DMT to indole-3-acetic acid (IAA), which is also reflected in the fact that the time of maximum concentration of IAA is similar to that of DMT. CONCLUSION: This review demonstrates that the PK of DMT in humans have been characterized to a limited extent, and publications lack details with regards to demographics, absolute doses, and PK parameters. Additional studies are necessary to investigate high intersubject variability and differences in exposure following bolus or prolonged infusion. Addressing these issues is essential for the development of DMT as a pharmacotherapeutic in neuropsychiatry.
Identifying the Optimal Sampling Strategy for the Bayesian Estimation of Vancomycin AUC in Adult Hematologic Cancer Patients.
Duong A, Le Blanc J, Projean D … +1 more , Marsot A
Clin Pharmacokinet · 2025 Feb · PMID 39827437 · Publisher ↗
BACKGROUND AND OBJECTIVE: The latest consensus recommends using the ratio between the area under the curve over 24 h (AUC) and minimal inhibitory concentration (MIC) as the therapeutic target for vancomycin in clinical p...
BACKGROUND AND OBJECTIVE: The latest consensus recommends using the ratio between the area under the curve over 24 h (AUC) and minimal inhibitory concentration (MIC) as the therapeutic target for vancomycin in clinical practice, with a Bayesian approach and population pharmacokinetic (popPK) model being particularly recommended. While using both post-dose peak concentration (C) and pre-dose concentration (C) is more accurate than C alone, the optimal sampling strategy for estimating AUC is still unclear. The objective of this study was to determine the best sampling time(s) to estimate AUC using the Bayesian approach in these specific adult hematologic cancer patients. METHODS: A virtual population (n = 7000) was simulated based on the distribution of the significant covariates (ideal body weight and estimated glomerular filtration rate) from the population used to develop the previous pharmacokinetic model. The dosing regimens from the Le Blanc et al. nomogram were used to generate, with NONMEM (v.7.5), simulated pharmacokinetic (PK) profiles of one loading dose followed by three maintenance doses (steady state). Strategies involving two samples taken during earlier maintenance doses and one sample taken at steady state were tested using the Bayesian approach to predict PK parameters. These strategies were then evaluated for their ability to predict AUC at steady state (AUC) RESULTS: For single-sample strategies, a sample taken anytime from 4 h post-dose can estimate AUC with precision similar to C (R ≈ 0.75), regardless of renal function (R ≈ 0.73-0.77). For two-sample strategies, taking samples at least midway through the dosing interval provides the highest precision for estimating AUC during the first two maintenance doses (R ≈ 0.75-0.77). In both strategies, using C did not yield as precise results as sampling midway through the dosing interval or at C. CONCLUSION: This study is the first to test multiple limited sampling strategies using a dosing nomogram stratified by renal function. The results show that vancomycin sampling can extend beyond traditional C and C without compromising the accuracy of maximum a posteriori Bayesian estimation of AUC, thereby providing an opportunity to investigate these limited sampling strategies combined with model-informed precision dosing in a clinical setting.
A Review of Vancomycin, Gentamicin, and Amikacin Population Pharmacokinetic Models in Neonates and Infants.
Albanell-Fernández M, Rodríguez-Reyes M, Bastida C … +1 more , Soy D
Clin Pharmacokinet · 2025 Jan · PMID 39821208 · Full text
Population pharmacokinetic (popPK) models are an essential tool when implementing therapeutic drug monitoring (TDM) and to overcome dosing challenges in neonates in clinical practice. Since vancomycin, gentamicin, and am...
Population pharmacokinetic (popPK) models are an essential tool when implementing therapeutic drug monitoring (TDM) and to overcome dosing challenges in neonates in clinical practice. Since vancomycin, gentamicin, and amikacin are among the most prescribed antibiotics for the neonatal population, we aimed to characterize the popPK models of these antibiotics and the covariates that may influence the pharmacokinetic parameters in neonates and infants with no previous pathologies. We searched the PubMed, Embase, Web of Science, and Scopus databases and the bibliographies of relevant articles from inception to the beginning of February 2024. The search identified 2064 articles, of which 68 met the inclusion criteria (34 for vancomycin, 21 for gentamicin, 13 for amikacin). A one-compartment popPK model was more frequently used to describe the pharmacokinetics of the three antibiotics (91.2% vancomycin, 76.9% gentamicin, 57.1% amikacin). Pharmacokinetic parameter (mean ± standard deviation) values calculated for a "typical" neonate weighing 3 kg were as follows: clearance (CL) 0.34 ± 0.80 L/h for vancomycin, 0.27 ± 0.49 L/h for gentamicin, and 0.19 ± 0.07 L/h for amikacin; volume of distribution (V): 1.75 ± 0.65 L for vancomycin, 1.54 ± 0.53 L for gentamicin, and 1.67 ± 0.27 L for amikacin for one-compartment models. Total body weight, postmenstrual age, and serum creatinine were common predictors (covariates) for describing the variability in CL, whereas only total body weight predominated for V. A single universal popPK model for each of the antibiotics reviewed cannot be implemented in the neonatal population because of the significant variability between them. Body weight, renal function, and postmenstrual age are important predictors of CL in the three antibiotics, and total body weight for V. TDM represents an essential tool in this population, not only to avoid toxicity but to attain the desired pharmacokinetic/pharmacodynamic index. The characteristics of the neonatal population, coupled with the lack of prospective studies and external validation of most models, indicate a need to continue investigating the pharmacokinetics of these antibiotics in neonates.
Clinical Pharmacokinetics of Psilocin After Psilocybin Administration: A Systematic Review and Post-Hoc Analysis.
Otto ME, van der Heijden KV, Schoones JW … +4 more , van Esdonk MJ, Borghans LGJM, Jacobs GE, van Hasselt JGC
Clin Pharmacokinet · 2025 Jan · PMID 39812743 · Full text
BACKGROUND AND OBJECTIVE: Psilocybin is currently being extensively studied as a potential therapeutic agent for multiple psychiatric disorders. Here, a systematic literature review of all published pharmacokinetic data...
BACKGROUND AND OBJECTIVE: Psilocybin is currently being extensively studied as a potential therapeutic agent for multiple psychiatric disorders. Here, a systematic literature review of all published pharmacokinetic data on the pharmacologically active metabolite of psilocybin, psilocin, is presented. METHODS: The review includes clinical studies that reported pharmacokinetic data and/or parameters after psilocybin administration in humans. In addition, raw pharmacokinetic data from these studies was requested and/or extracted to further compare results across studies. RESULTS: In total, 309 publications were identified, of which 19 publications were ultimately included, which covered 12 unique clinical datasets. Except for one study that investigated intravenous psilocybin, all included studies administered psilocybin orally. Psilocybin acts as a pro-drug and is rapidly absorbed and transformed to psilocin after oral administration. In the majority of studies, unconjugated psilocin was measured while some also measured conjugated and total concentrations. Psilocin's biphasic concentration-time profiles demonstrates fast and extensive disposition with an apparent distribution volume of 505-1267 L and a terminal half-life of 1.23-4.72 h. Only 1.5-3.4% of the dose is excreted as psilocin in urine. Psilocin is mainly transformed to 4-hydroxyindole-3-acetic acid and in less amounts to conjugated psilocin, where 4-hydroxyindole-3-acetic acid formation may occur prior to systemic psilocin absorption. Information on the absolute bioavailability of psilocin was limited, and estimated at 55% in one study. No covariates nor food effects have been reported, based on four studies with known fasting status. CONCLUSIONS: Overall, we found the pharmacokinetic parameters of psilocin to be consistent between studies. This review may guide the further clinical development of psilocybin-based therapies.
Population Pharmacokinetics of Telmisartan in Healthy Subjects and Hypertensive Patients.
Jeong IH, Ryu S, Han N … +2 more , Staatz CE, Baek IH
Clin Pharmacokinet · 2025 Feb · PMID 39808372 · Publisher ↗
BACKGROUND AND OBJECTIVE: Telmisartan exhibits significant pharmacokinetic (PK) variability, but it remains unclear whether its PK profile is altered in hypertensive patients. This study aimed to characterize telmisartan...
BACKGROUND AND OBJECTIVE: Telmisartan exhibits significant pharmacokinetic (PK) variability, but it remains unclear whether its PK profile is altered in hypertensive patients. This study aimed to characterize telmisartan PKs by conducting a meta-analysis and developing a pooled population PK model based on data from healthy subjects and hypertensive patients. METHODS: Relevant literature was identified by a systematic approach. Eighteen studies were selected for analysis, which included 394 healthy subjects receiving single doses of telmisartan, 190 healthy subjects receiving repeated doses, along with 295 hypertensive patients receiving repeated doses. Pooled population PK analysis incorporated 20 mean concentration-time profiles from 14 studies. Meta-analyses were performed using OpenMeta-Analyst, and population PK modeling was performed using NONMEM. RESULTS: Repeated telmisartan doses increased peak plasma concentrations. However, other noncompartmental PK parameters remained consistent across healthy and hypertensive populations. Telmisartan PKs were best described using a two-compartment model with first-order absorption and elimination in pooled analysis. Typical PK parameter values for apparent clearance (CL/F), apparent central and peripheral volumes of distribution (V/F and V/F), absorption rate constant (k), and absorption lag time were 18.3 L/h, 20.7 L, 360 L, 0.183 h and 0.228 h, respectively. Interindividual variabilities in CL/F, V/F, and k were 84%, 122%, and 106%, respectively. Covariate analysis revealed significantly lower CL/F (63.7%) and V/F (90.3%) values in hypertensive patients than healthy subjects. CONCLUSION: These findings quantified the variability of telmisartan PK profile and highlighted the differences between healthy individuals and hypertensive patients, suggesting the need for optimized dosage strategies to improve therapeutic outcomes.
Improving Understanding of Fexofenadine Pharmacokinetics to Assess Pgp Phenotypic Activity in Older Adult Patients Using Population Pharmacokinetic Modeling.
Gaspar F, Jacost-Descombes C, Gosselin P … +6 more , Reny JL, Guidi M, Csajka C, Samer C, Daali Y, Terrier J
Clin Pharmacokinet · 2025 Feb · PMID 39798016 · Full text
BACKGROUND AND OBJECTIVE: Fexofenadine is commonly used as a probe substrate to assess P-glycoprotein (Pgp) activity. While its use in healthy volunteers is well documented, data in older adult and polymorbid patients ar...
BACKGROUND AND OBJECTIVE: Fexofenadine is commonly used as a probe substrate to assess P-glycoprotein (Pgp) activity. While its use in healthy volunteers is well documented, data in older adult and polymorbid patients are lacking. Age- and disease-related physiological changes are expected to affect the pharmacokinetics of fexofenadine. This study aims to investigate the pharmacokinetics of fexofenadine in hospitalized older adult patients as a potential marker of Pgp activity, using data from the OptimAT study (ClinicalTrials.gov identifier: NCT03477331). METHODS: Population pharmacokinetic (popPK) modeling was conducted using data from 449 hospitalized patients with a median age of 71 years (range: 25-97) and 10 healthy volunteers (median age: 23 years, range: 20-36). Fexofenadine plasma concentrations were analyzed using a refined two-compartment model with sequential zero/first-order absorption, while investigating the impact of covariates such as age, renal function, and Pgp inhibitors on fexofenadine pharmacokinetics. RESULTS: Age, renal insufficiency, and Pgp inhibitors significantly influenced fexofenadine exposure. Renal function was a key factor, with AUC increasing by 79% in mild-to-moderate and by 154% in moderate-to-severe renal impairment compared with normal renal function. Co-administration of Pgp inhibitors led to a 35% increase in AUC. Across chronic kidney disease (CKD) stages, age, and Pgp inhibitor status, fexofenadine AUC ratio ranged from 1.15 (stage 1, 20-30 years) to 4.59 (stage 5, 91-100 years, with Pgp inhibitors), relative to a reference subject of 20 years, normal renal function, and no Pgp inhibitors. CONCLUSION: Clinicians should consider the risk of Pgp substrate accumulation in older adults, particularly those with advanced renal impairment. We propose typical values stratified by age and renal function to assist in interpreting Pgp phenotyping using fexofenadine exposure, thereby supporting drug optimization in this population. Further studies are needed to explore underlying mechanisms, such as reduced Pgp activity or expression.
Influence of Ageing on the Pharmacodynamics and Pharmacokinetics of Chronically Administered Medicines in Geriatric Patients: A Review.
Ngcobo NN
Clin Pharmacokinet · 2025 Mar · PMID 39798015 · Full text
As people age, the efficiency of various regulatory processes that ensure proper communication between cells and organs tends to decline. This deterioration can lead to difficulties in maintaining homeostasis during phys...
As people age, the efficiency of various regulatory processes that ensure proper communication between cells and organs tends to decline. This deterioration can lead to difficulties in maintaining homeostasis during physiological stress. This includes but is not limited to cognitive impairments, functional difficulties, and issues related to caregivers which contribute significantly to medication errors and non-adherence. These factors can lead to higher morbidity, extended hospital stays, reduced quality of life, and even mortality. The decrease in homeostatic capacity varies among individuals, contributing to the greater variability observed in geriatric populations. Significant pharmacokinetic and pharmacodynamic alterations accompany ageing. Pharmacokinetic changes include decreased renal and hepatic clearance and an increased volume of distribution for lipid-soluble drugs, which prolong their elimination half-life. Pharmacodynamic changes typically involve increased sensitivity to various drug classes, such as anticoagulants, antidiabetic and psychotropic medications. This review examines the primary age-related physiological changes in geriatrics and their impact on the pharmacokinetics and pharmacodynamics of medications.
Clinical Pharmacokinetics of Antitubercular Drugs in the Overweight and Obese Population: Implications for Dosage Adjustments.
Prager M, Al Jalali V, Zeitlinger M
Clin Pharmacokinet · 2025 Feb · PMID 39792209 · Full text
The rise in global obesity prevalence has increased the need to understand the pharmacokinetics of drugs in overweight and obese individuals. Tuberculosis remains a significant health challenge, and its treatment outcome...
The rise in global obesity prevalence has increased the need to understand the pharmacokinetics of drugs in overweight and obese individuals. Tuberculosis remains a significant health challenge, and its treatment outcomes can be influenced by the pharmacokinetic profiles of antitubercular agents. This literature review aims to point out the clinical pharmacokinetics of antitubercular drugs in the overweight and obese patient population, highlighting considerations for potential dosage adjustments. We conducted a comprehensive search of the PubMed US National Library of Medicine from inception to January 2024. Articles focusing on the pharmacokinetics of antitubercular agents used for both drug-susceptible and multidrug-resistant tuberculosis in overweight and obese adults were included. In total, 349 scientific articles were identified and examined for human pharmacokinetic parameters. Of these, 19 were included in this article. To highlight potential differences, pharmacokinetic data for normal-weight tuberculosis patients are also presented, albeit selectively. In general, pharmacokinetic studies of antitubercular agents in overweight and obese individuals are lacking. Fixed-dose combinations often used in the treatment of drug-susceptible tuberculosis are not recommended when treating these population groups. Rather, individual dosing based on therapeutic drug monitoring and the known solubility of the substance should be considered. To improve the management of tuberculosis in overweight and obese patients, there is an urgent need for pharmacokinetic studies and, ultimately, adequate dosing in this patient population, especially given the increasing prevalence of obesity.
Physiologically Based Pharmacokinetic Model of Cefotaxime in Patients with Impaired Renal Function.
Zbib F, Deschamps A, Velly L … +3 more , Blin O, Guilhaumou R, Gattacceca F
Clin Pharmacokinet · 2025 Feb · PMID 39762592 · Publisher ↗
BACKGROUND: Cefotaxime is a widely prescribed cephalosporin antibiotic used to treat various infections. It is mainly eliminated unchanged by the kidney through tubular secretion and glomerular filtration. Therefore, a r...
BACKGROUND: Cefotaxime is a widely prescribed cephalosporin antibiotic used to treat various infections. It is mainly eliminated unchanged by the kidney through tubular secretion and glomerular filtration. Therefore, a reduction of kidney function may increase exposure to the drug and induce toxic side effects. OBJECTIVES: The objectives of this study were to develop a physiologically based pharmacokinetic (PBPK) model of cefotaxime in healthy European adults, to mechanistically describe the impact of chronic kidney disease (CKD) on cefotaxime pharmacokinetics, and to assess the applicability of the model to patients requiring intensive care. METHODS: Using PK-Sim software, we developed a PBPK model for cefotaxime, including basolateral and apical renal transporters and renal esterases, in healthy subjects and then extrapolated to patients with CKD by incorporating pathophysiological changes and reductions in activity of drug-metabolizing enzymes and transporters into the model. We then evaluated the predictive performance of the model in patients requiring intensive care using clinical routine data. RESULTS: Model predictions were considered adequate in healthy subjects and patients with CKD, with predicted-to-observed area under the curve ratios within the two-fold acceptance criterion. Mean prediction error and mean absolute prediction error did not exceed ± 30 and 30%, respectively, except in patients with stage 4 CKD, where they were 70.5 and 75.6%, respectively. The model showed good predictive performance when applied to patients requiring intensive care, but its clinical applicability in this population needs to be further evaluated. CONCLUSION: We successfully developed whole-body PBPK models to predict cefotaxime pharmacokinetics in different populations. These models represent an additional step toward improving personalized cefotaxime dosing regimens in vulnerable populations.
A Pooled Pharmacokinetic Analysis for Piperacillin/Tazobactam Across Different Patient Populations: From Premature Infants to the Elderly.
Kong D, Roberts JA, Lipman J … +17 more , Taccone FS, Cohen-Wolkowiez M, Sime FB, Tsai D, De Cock PAJG, Jaruratanasirikul S, Dhaese SAM, Udy AA, Felton TW, Michelet R, Thibault C, Koomen JV, Eleveld DJ, Struys MMRF, De Waele JJ, Colin PJ, PIP/TAZ Consortium
Clin Pharmacokinet · 2025 Jan · PMID 39722108 · Full text
BACKGROUND AND OBJECTIVES: The pharmacokinetics (PK) of piperacillin/tazobactam (PIP/TAZ) is highly variable across different patient populations and there are controversies regarding non-linear elimination as well as th...
BACKGROUND AND OBJECTIVES: The pharmacokinetics (PK) of piperacillin/tazobactam (PIP/TAZ) is highly variable across different patient populations and there are controversies regarding non-linear elimination as well as the fraction unbound of PIP (f). This has led to a plethora of subgroup-specific models, increasing the risk of misusing published models when optimising dosing regimens. In this study, we aimed to develop a single model to simultaneously describe the PK of PIP/TAZ in diverse patient populations and evaluate the current dosing recommendations by predicting the PK/pharmacodynamics (PD) target attainment throughout life. METHODS: Population PK models were separately built for PIP and TAZ based on data from 13 studies in various patient populations. In the development of those single-drug models, postnatal age (PNA), postmenstrual age (PMA), total body weight (TBW), height, and serum creatinine (SCR) were tested as covariates. Subsequently, a combined population PK model was established and the correlations between the PK of PIP and TAZ were tested. Monte Carlo simulations were performed based on the final combined model to evaluate the current dosing recommendations. RESULTS: The final combined model for PIP/TAZ consisted of four compartments (two for each drug), with covariates including TBW, PMA, and SCR. For a 70-kg, 35-year-old patient with SCR of 0.83 mg L, the PIP values for V, CL, V and Q were 10.4 L, 10.6 L h, 11.6 L and 15.2 L h, respectively, and the TAZ values were 10.5 L, 9.58 L h, 13.7 L and 16.8 L h, respectively. The CL for both drugs show maturation in early life, reaching 50% at 54.2 weeks PMA. With advancing age, CL of TAZ declines to 50% at 61.6 years PMA, whereas CL of PIP declines more slowly, reaching 50% at 89.1 years PMA. The f was estimated as 64.5% and non-linear elimination was not supported by our data. The simulation results indicated considerable differences in PK/PD target attainment for different patient populations under current recommended dosing regimens. CONCLUSIONS: We developed a combined population PK model for PIP/TAZ across a broad range of patients covering the extremes of patient characteristics. This model can be used as a robust a priori model for Bayesian forecasting to achieve individualised dosing. The simulations indicate that adjustments based on the allometric theory as well as maturation and decline of CL of PIP may help the current dosing recommendations to provide consistent target attainment across patient populations.
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