Population Pharmacokinetics of Sertraline in Healthy Subjects: a Model-Based Meta-analysis

Alhadab, Ali A.; Brundage, Richard C.

doi:10.1208/s12248-020-00455-y

Cited by 14 publications

(13 citation statements)

References 54 publications

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“…plasma data from 1.15 to 1.05 in order to reproduce sertraline oral plasma concentration‐time data. Accounting for the saturable elimination, as suggested by in vitro studies, improved sertraline bioavailability prediction, which matches our previous MBMA results ( Figure ) 31 . However, with repeated oral dosing, sertraline bioavailability was no longer dependent on dose.…”

Section: Discussionsupporting

confidence: 88%

“…The final parameters for each sertraline dose and the assessment of prediction accuracy are presented in Table 3 . Using the final parameters for each dose, the PBPK model predicted similar sertraline oral bioavailability to what was estimated previously by our MBMA 31 after single dose administration, further supporting the predictive performance of the current PBPK model ( Figure ).…”

Section: Resultssupporting

confidence: 82%

“…Sertraline i.v. and oral plasma concentration‐time data in healthy subjects from a model‐based meta‐analysis (MBMA) that we performed earlier were used to develop and qualify a sertraline PBPK model 31 . Briefly, the model was developed using the i.v.…”

Section: Methodsmentioning

confidence: 99%

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Physiologically‐Based Pharmacokinetic Model of Sertraline in Human to Predict Clinical Relevance of Concentrations at Target Tissues

Alhadab

Brundage

2020

Clin Pharma and Therapeutics

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Significant in vitro and in vivo evidence supports the potential use of sertraline as an anticancer and antimicrobial agent. Yet, it is unknown whether effective sertraline concentrations are clinically achieved at therapeutic doses. The study objectives were to develop a physiologically‐based pharmacokinetic (PBPK) model of sertraline and estimate the probability of achieving effective concentrations in various human tissues. A generic PBPK model consisting of perfusion‐limited compartments representing the body organs linked together by blood flows and incorporated with clearance, tissue distribution, and absorption models was implemented in R using the mrgsolve package. Sertraline clearance and volume of distribution were first optimized from i.v. plasma concentration data then absorption and bioavailability were optimized from oral data. Predicted unbound sertraline concentrations at steady‐state in human tissues did not reach concentrations determined in vitro, indicating therapeutic doses of sertraline are unlikely to produce concentrations required for anticancer and antimicrobial activities in humans.

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Section: Discussionsupporting

confidence: 88%

Section: Resultssupporting

confidence: 82%

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Physiologically‐Based Pharmacokinetic Model of Sertraline in Human to Predict Clinical Relevance of Concentrations at Target Tissues

Alhadab

Brundage

2020

Clin Pharma and Therapeutics

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Section: Discussionmentioning

confidence: 99%

“…This phenomenon might be caused by the saturation of first-pass metabolism which was also observed in other SSRIs such as paroxetine and/or by the saturation of the P-glycoprotein (P-gp) transporter in the gastrointestinal track associated with the absorption of DA-8031. [23][24][25] The genetic polymorphism of CYP2D6 and CYP2C19 can influence the metabolism of SSRIs, affecting interindividual differences in PK parameters and eventually affecting the drug efficacy and safety. 17 These polymorphisms also had an impact on the metabolism of DA-8031.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Tolerability and Pharmacogenetics of DA-8031 After Multiple Ascending Doses in Healthy Male Subjects

Hwang

Lee²,

Cho³

et al. 2021

DDDT

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Purpose DA-8031 is a novel selective serotonin reuptake inhibitor for the treatment of premature ejaculation. This study investigated the pharmacokinetics, safety and tolerability of multiple oral doses of DA-8031. In addition, a genetic analysis was explored to evaluate the effect of genetic polymorphisms on the pharmacokinetics of DA-8031. Subjects and Methods A dose block-randomized, double-blind, placebo-controlled study was conducted in 3 dose groups with 20, 30 and 40 mg of DA-8031. Healthy male subjects were randomized to DA-8031 or placebo at a 4:1 ratio in each dose group of 10 subjects by oral administration once daily for 7 consecutive days. Serial blood and urine samples were collected for the pharmacokinetic evaluation, and the pharmacokinetic-related genes were analyzed by DMET TM plus. A safety evaluation was conducted including adverse events (AEs) monitoring and 12-lead electrocardiogram (ECG). Results The plasma DA-8031 concentration reached the maximum concentration (C max ) in 2.2 to 3.0 h and was eliminated with a mean half-life of 25.5 to 26.7 h at steady state. The accumulation index of DA-8031 ranged 2.3 to 2.8. The systemic exposure of DA-8031 of the CYP2D6 intermediate metabolizer (IM) was significantly higher compared to the CYP2D6 poor metabolizer (PM). There were no clinically significant QTc interval changes, and all the adverse events were mild. Conclusion After multiple oral doses of DA-8031 20, 30, and 40 mg in this study, the systemic exposure of DA-8031 increased in a more than dose-proportional manner with the increasing doses, and DA-8031 was generally well tolerated. In addition, the genetic polymorphisms of CYP2D6 have an impact on the pharmacokinetics of DA-8031.

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Applications of Model-Based Meta-Analysis in Drug Development

Chan¹,

Peskov

Song

2022

Pharm Res

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Model-based meta-analysis (MBMA) is a quantitative approach that leverages published summary data along with internal data and can be applied to inform key drug development decisions, including the benefit-risk assessment of a treatment under investigation. These risk–benefit assessments may involve determining an optimal dose compared against historic external comparators of a particular disease indication. MBMA can provide a flexible framework for interpreting aggregated data from historic reference studies and therefore should be a standard tool for the model-informed drug development (MIDD) framework.In addition to pairwise and network meta-analyses, MBMA provides further contributions in the quantitative approaches with its ability to incorporate longitudinal data and the pharmacologic concept of dose–response relationship, as well as to combine individual- and summary-level data and routinely incorporate covariates in the analysis.A common application of MBMA is the selection of optimal dose and dosing regimen of the internal investigational molecule to evaluate external benchmarking and to support comparator selection. Two case studies provided examples in applications of MBMA in biologics (durvalumab + tremelimumab for safety) and small molecule (fenebrutinib for efficacy) to support drug development decision-making in two different but well-studied disease areas, i.e., oncology and rheumatoid arthritis, respectively.Important to the future directions of MBMA include additional recognition and engagement from drug development stakeholders for the MBMA approach, stronger collaboration between pharmacometrics and statistics, expanded data access, and the use of machine learning for database building. Timely, cost-effective, and successful application of MBMA should be part of providing an integrated view of MIDD.

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Population Pharmacokinetics of Sertraline in Healthy Subjects: a Model-Based Meta-analysis

Cited by 14 publications

References 54 publications

Physiologically‐Based Pharmacokinetic Model of Sertraline in Human to Predict Clinical Relevance of Concentrations at Target Tissues

Physiologically‐Based Pharmacokinetic Model of Sertraline in Human to Predict Clinical Relevance of Concentrations at Target Tissues

Pharmacokinetics, Tolerability and Pharmacogenetics of DA-8031 After Multiple Ascending Doses in Healthy Male Subjects

Applications of Model-Based Meta-Analysis in Drug Development

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