A Nonlinear Mixed Effects Pharmacokinetic Model for Dapagliflozin and Dapagliflozin 3‐<i>O</i>‐glucuronide in Renal or Hepatic Impairment

Walt, J-S van der; Yang, Hong; Zhang, L; Pfister, Marc; Boulton, David W.; Karlsson, Mats O.

doi:10.1038/psp.2013.20

Cited by 23 publications

(24 citation statements)

References 20 publications

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“…Although the primary focus of the analysis was to characterize the difference in clearance by phenotype, both the large variability in the absorption phase and sparse observations for the absorption phase were strongly affecting the estimation. A more complex absorption model could address this variability and improve clearance estimate, the data set, however, was not enough rich to support complex absorption models, 15,16 F I G U R E Visual predictive check. One thousand simulated data sets comprising the equal number of actual observations for each setting are generated from the model using mrgsolve (Ver.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetic analysis of esomeprazole in Japanese subjects with various CYP2C19 phenotypes

et al. 2020

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What is known and objective Esomeprazole, the S‐isomer of omeprazole, is a proton pump inhibitor which has been approved by over 125 countries, also known as NEXIUM®. Esomeprazole was developed to provide further improvement on efficacy for acid‐related diseases with higher systemic bioavailability due to the less first‐pass metabolism and lower plasma clearance. Esomeprazole is primarily metabolized by CYP2C19. Approximately <1% of Caucasians and 5%‐10% of Asians have absent CYP2C19 enzyme activity. Although the influence of various CYP2C19 phenotypes on esomeprazole pharmacokinetics has been studied, this is the first report in the Japanese population where 27 low CYP2C19 metabolizers were included. Methods In this study, a population PK model describing the PK of esomeprazole was developed to understand the difference of CYP2C19 phenotypes on clearance in the Japanese population. The model quantitatively assessed the influence of CYP2C19 phenotype on esomeprazole PK in healthy Japanese male subjects after receiving repeated oral dosing. The inhibition mechanism of esomeprazole on CYP2C19 activity was also included in the model. Results and discussion CYP2C19 phenotype and dose were found as statistically significant covariates on esomeprazole clearance. The apparent clearance at 10‐mg dose was 17.32, 9.77 and 7.37 (L/h) for homozygous extensive metabolizer, heterozygous extensive metabolizer and poor metabolizer subjects, respectively. And the apparent clearance decreased as dose increased. What is new and conclusion The established population PK model well described the esomeprazole PK and model‐predicted esomeprazole PK was in good agreement with external clinical data, suggesting the robustness and applicability of the current model for predicting esomeprazole PK.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetic analysis of esomeprazole in Japanese subjects with various CYP2C19 phenotypes

et al. 2020

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“…MTT represents the average time for a drug molecule to transit from the first transit compartment to the absorption compartment. The relationship between MTT, n and k tr is shown [8,9]:…”

Section: Transl Clin Pharmacolmentioning

confidence: 99%

Population pharmacokinetic analysis of the multiple peaks phenomenon in sumatriptan

Lee

Lim

Seong

et al. 2015

Transl Clin Pharmacol

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+The first two authors contributed equally to this work.The objective of this study was to develop a population pharmacokinetic (PK) model for sumatriptan, which frequently shows an atypical absorption profile with multiple peaks. Sumatriptan, a selective agonist for the vascular serotonin (5-HT1) receptor that causes vasoconstriction of the cerebral arteries, is used for the acute treatment of migraine attack with or without aura. Despite its relatively high between-subject variability, few reports have addressed PK modeling of sumatriptan. Plasma data obtained after a single 50-mg oral dose of sumatriptan in 26 healthy Korean male subjects were used. Blood samples were collected 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 h after dosing. Plasma sumatriptan concentrations were analyzed using UPLC/MS/MS. Population PK analysis was performed using plasma concentration data for sumatriptan with NON-MEM (ver. 7.2). A total of 364 concentrations of sumatriptan were captured by a one-compartment model with first-order elimination, and a combined transit compartment model and first-order absorption with lag time was successful in describing the PK with multiple peaks in the absorption phase of sumatriptan. The creatinine clearance as a covariate significantly (P < 0.01) influenced the absorption fraction (f ). The final model was validated through a visual predictive check and bootstrapping with no serious model misspecification.

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“…In another example, a semimechanistic POPPK model was developed for dapagliflozin combining data from an RI, hepatic impairment, and a Phase III clinical trial in type 2 diabetes. Although dapagliflozin is not approved for patients with CrCl < 60 mL/min/1.73 m 2 due to lack of efficacy and increased safety concerns, simulations based on this model as well as literature findings helped explain the greater systemic exposure of dapagliflozin in subjects with moderate and severe RI when compared with subjects with normal renal function. A similar approach was recently conducted for metformin in T2DM patients with various degrees of RI.…”

Section: Analysis Of Pharmacokinetics and Pharmacodynamics Of Drugs Imentioning

confidence: 99%

Emerging areas of research in the assessment of pharmacokinetics in patients with chronic kidney disease

Tortorici

Cutler

Hazra

et al. 2015

The Journal of Clinical Pharma

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Chronic kidney disease (CKD) has been shown to alter the pharmacokinetics of drugs that are eliminated not only via the renal pathway but also by nonrenal clearance and transport. Dosing recommendations in subjects with CKD have historically come from small pharmacokinetic (PK) studies, which have been insulated from the broader clinical development strategy. Opportunities for prospective strategic integration of both preclinical and clinical data on drug clearance mechanisms, model-based approaches, and clinical knowledge of therapeutic index are therefore often missed in designing and analyzing the results of PK studies in subjects with CKD, and eventually providing dosing recommendations. These considerations are valuable in designing informative PK studies in subjects with CKD, as well as for guiding kidney function-related inclusion/exclusion criteria in the broader clinical program and ultimately defining dosing guidelines that optimize benefit-risk balance for these special patient populations based on all available data. This paper offers points to consider for drug developers to increase adoption of a contemporary multidisciplinary approach, which includes key considerations on study design and conduct, methodologies for analysis (population PK and physiologically based PK modeling), and a roadmap to interpret the effect of kidney function on the overall benefit-risk profile of drugs in development.

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A Nonlinear Mixed Effects Pharmacokinetic Model for Dapagliflozin and Dapagliflozin 3‐O‐glucuronide in Renal or Hepatic Impairment

Cited by 23 publications

References 20 publications

Population pharmacokinetic analysis of esomeprazole in Japanese subjects with various CYP2C19 phenotypes

Population pharmacokinetic analysis of esomeprazole in Japanese subjects with various CYP2C19 phenotypes

Population pharmacokinetic analysis of the multiple peaks phenomenon in sumatriptan

Emerging areas of research in the assessment of pharmacokinetics in patients with chronic kidney disease

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