Case-control matching-guided exposure-efficacy relationship for avelumab in patients with urothelial carcinoma.

Exposure-response (E-R) analyses are an integral component of understanding the benefit/risk profile of novel oncology therapeutics. These analyses are typically conducted using data from the treatment arm to characterize the relationship between drug exposure (low vs. high) and efficacy or safety outcomes.

Analysis of US Food and Drug Administration Oncology Approvals on the Characterization of Hepatic Impairment Effect and Dosing Recommendations.

Patients with cancer and advanced hepatic impairment (HI) (i.e., moderate and severe impairment) are often excluded from first-in-patient, phase II, and phase III studies.

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.

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.

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.

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 log CFU/mL from baseline.

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 [] of <10 mg/liter)- and efficacy (free, unbound plasma concentration-to-MIC ratio [/MIC] of ≥8)-linked targets. In addition, an adaptive resistance PD (ARPD) model of 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.

Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study.

Background: Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus.

Methods: In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014.

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.