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

Sertraline pharmacokinetics is poorly understood and highly variable due to large between-subject variability with inconsistent reports for oral bioavailability. The study objective was to characterize sertraline pharmacokinetics by developing and validating a sertraline population pharmacokinetic (PK) model in healthy subjects using published clinical PK data. We carried a systematic literature search in PubMed in October 2015 and identified 27 pharmacokinetic studies of sertraline conducted in healthy adult subjects and reported in the English language. Sixty mean plasma concentration-time profiles made of 748 plasma concentrations following IV, single, and multiple oral doses ranging from 5 to 400 mg were extracted and analyzed for dose proportionality by a log-linear model and fitted to a 2-compartment pharmacokinetic model in NONMEM using a model-based meta-analysis (MBMA) approach. After a single oral dose, sertraline Cmax and AUC∞ increased with dose proportionally between 50 and 200 mg, and bioavailability increased nonlinearly with dose from 5 to 50 mg and plateaued afterwards while Tmax and t1/2 did not change with dose. Following multiple oral doses, Cmax and AUC∞ increased proportionally with dose across the entire dose range (5-200 mg) while bioavailability, Tmax, and t1/2 remained constant with dose. Sertraline absorption was time-dependent and best described by a sigmoidal Emax function of time after dose. Study findings indicate that sertraline PK is linear in healthy adult subjects at doses ≥ 50 mg, and exposures were nonlinear only after single oral doses < 50 mg likely due to reduced bioavailability.

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

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.

Semimechanistic Modeling to Guide Venetoclax Coadministration with Ritonavir and Digoxin.

Venetoclax is a cytochrome P450, family 3, subfamily A (CYP3A) substrate and was shown to inhibit P-gp efflux transporters in vitro. To quantify the impact of CYP3A inhibition by ritonavir on venetoclax disposition and P-gp inhibition by venetoclax on digoxin pharmacokinetics, two semimechanistic drug-drug interaction (DDI) models of venetoclax were developed using clinical data from healthy volunteers who received subtherapeutic doses of venetoclax with ritonavir 50-100 mg or digoxin 0.5 mg. These models were then used to assess the magnitude of interaction at therapeutic venetoclax doses and to explore various clinical dosing strategies that maintain venetoclax and digoxin concentrations within their respective therapeutic windows. Simulations demonstrated that venetoclax dose reductions of at least 75% are needed when venetoclax is coadministered with ritonavir and administering digoxin at least 2 hours before venetoclax would minimize DDI. Semimechanistic modeling leveraging clinical data is a plausible approach to predict DDI and propose dose adjustments, and administration time of interacting drugs.

Pharmacokinetics-pharmacodynamics of sertraline as an antifungal in HIV-infected Ugandans with cryptococcal meningitis.

The ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis in HIV-infected Ugandan patients. The present study is a post hoc pharmacokinetic-pharmacodynamic analysis of the ASTRO-CM pilot study to provide insight into sertraline exposure-response-outcome relationships. We performed a population pharmacokinetic analysis using sertraline plasma concentration data and correlated various predicted PK-PD indices with the percentage change in log10 CFU/mL from baseline. Sertraline clearance was 1.95-fold higher in patients receiving antiretroviral (ART), resulting in 49% lower drug exposure. To quantify the clinical benefit of sertraline, we estimated rates of fungal clearance from cerebrospinal fluid (CSF) of ASTRO-CM patients using Poisson model and compared the clearance rates to a historical control study (COAT) in which patients received standard Cryptococcus therapy of amphotericin B (0.7-1.0 mg/kg per day) and fluconazole (800 mg/day) without sertraline. Adjunctive sertraline significantly increased CSF fungal clearance rate compared to COAT trial and sertraline effect was dose-independent with no covariate found to affect fungal clearance including ART. Study findings suggest sertraline response could be mediated by different mechanisms than directly inhibiting the initiation of protein translation as previously suggested; this is supported by the prediction of unbound sertraline concentrations is unlikely to reach MIC concentrations in the brain. Study findings also recommend against the use of higher doses of sertraline, especially those greater than the maximum FDA-approved daily dose (200 mg/day), since they unlikely provide any additional benefits and come with greater costs and risk of adverse events.

Amikacin Pharmacokinetic-Pharmacodynamic Analysis in Pediatric Cancer Patients.

We performed pharmacokinetic-pharmacodynamic (PK-PD) and simulation analyses to evaluate a standard amikacin dose of 15 mg/kg once daily in children with cancer and to determine an optimal dosing strategy. A population pharmacokinetic model was developed from clinical data collected in 34 pediatric patients and used in a simulation study to predict the population probability of various dosing regimens to achieve accepted safety (steady-state unbound trough plasma concentration [fCmin] of <10 mg/liter)- and efficacy (free, unbound plasma concentration-to-MIC ratio [fCmax/MIC] of ≥8)-linked targets. In addition, an adaptive resistance PD (ARPD) model of Pseudomonas aeruginosa was built based on literature time-kill curve data and linked to the PK model to perform PK-ARPD simulations and compare results with those of the probability approach. Using the probability approach, an amikacin dose of 60 mg/kg administered once daily is expected to achieve the target fCmax/MIC in 80% of pediatric patients weighing 8 to 70 kg with a 97.5% probability, and almost all patients were predicted to have fCmin of <10 mg/liter. However, PK-ARPD simulation predicted that 60 mg/kg/day is unlikely to suppress bacterial resistance with repeated dosing. Furthermore, PK-ARPD simulation suggested that amikacin at 90 mg/kg, given in two divided doses (45 mg/kg twice a day), is expected to hit safety and efficacy targets and is associated with a lower rate of bacterial resistance. The disagreement between the two methods is due to the inability of the probability approach to predict development of drug resistance with repeated dosing. This originates from the use of PK-PD indices based on the MIC that neglects measurement errors, ignores the time course dynamic nature of bacterial growth and killing, and incorrectly assumes the MIC to be constant during treatment.

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda.

Cryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with a CD4 count of <100 cells/µl, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010 and 2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998 to 1999 that reported an MIC50 of 4 µg/ml and an MIC90 of 8 µg/ml prior to widespread human fluconazole and agricultural azole fungicide usage, we report an upward shift in the fluconazole MIC50 to 8 µg/ml and an MIC90 value of 32 µg/ml, with 31% of isolates with a fluconazole MIC of ≥ 16 µg/ml. We observed an amphotericin B MIC50 of 0.5 µg/ml and an MIC90 of 1 µg/ml, of which 99.5% of isolates (197 of 198 isolates) were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and fluconazole combination induction therapy. We also analyzed Cryptococcus susceptibility to sertraline, with an MIC50 of 4 µg/ml, suggesting that sertraline is a promising oral, low-cost, available, novel medication and a possible alternative to fluconazole. Although the CLSI broth microdilution assay is ideal to standardize results, limit human bias, and increase assay capacity, such assays are often inaccessible in low-income countries. Thus, we also developed and validated an assay that could easily be implemented in a resource-limited setting, with similar susceptibility results (P = 0.52).