Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in paediatric liver transplant recipients.

Aims: The objectives of this study were to develop a population pharmacokinetic (PopPK) model for tacrolimus in paediatric liver transplant patients and determine optimal sampling strategies to estimate tacrolimus exposure accurately.

Methods: Twelve hour intensive pharmacokinetic profiles from 30 patients (age 0.4-18.

Limited sampling strategies for monitoring tacrolimus in pediatric liver transplant recipients.

Objective: To develop and validate limited sampling strategies (LSSs) for tacrolimus in pediatric liver transplant recipients.

Methods: Thirty-six 12-hour pharmacokinetic profiles from 28 pediatric liver transplant recipients (0.4-18.

Increased risk of myocardial infarction associated with angiotensin-converting enzyme gene polymorphism is age dependent.

The angiotensin-converting enzyme (ACE) gene is a candidate genetic locus for coronary artery disease (CAD). Studies investigating the relationship between the ACE-insertion/deletion (I/D) gene polymorphism and myocardial infarction (MI) have been inconsistent. The authors hypothesized that age may be an important modulating factor in this relationship.

Population pharmacokinetics of intravenous pantoprazole in paediatric intensive care patients.

What Is Already Known About This Subject: The use of intravenous pantoprazole, a proton pump inhibitor, has been increasing in the paediatric intensive care unit. Despite this increased use, data on the disposition of intravenous pantoprazole in paediatric intensive care patients are very scarce.

What This Study Adds: Our population approach has determined the pharmacokinetic parameters of intravenous pantoprazole in paediatric intensive care patients and the relative importance of factors influencing its disposition.

Inhibitory effects of propafenone on the pharmacokinetics of caffeine in humans.

CYP1A2 is involved in the metabolism of both caffeine and propafenone, a class Ic antiarrhythmic agent. Despite the widespread consumption of caffeine, drug-drug interactions with this agent are often overlooked. This study investigated effects of propafenone on the pharmacokinetics of caffeine.

Multilocus genetic interactions and response to efavirenz-containing regimens: an adult AIDS clinical trials group study.

Objective: For the HIV-1 reverse transcriptase inhibitor efavirenz, variant drug transporter gene ABCB1 may predict virologic response but not plasma efavirenz exposure. Conversely, variant drug metabolizing enzyme gene CYP2B6 predicts greater plasma efavirenz exposure but not virologic response. We examined whether long-term responses to efavirenz, and/or plasma efavirenz exposure, are better predicted by multilocus genetic interactions than by individual polymorphisms.

A non-linear mixed effect dynamic model incorporating prior exposure and adherence to treatment to describe long-term therapy outcome in HIV-patients.

Long term therapy with antiretroviral agents in HIV-infected patients often result in failure to suppress the virus load. Imperfect adherence to prescribed antiviral drugs is an important factor explaining the resurgence of virus. A better understanding of the factors responsible for the virological failure is important for the development of new treatment strategies.

Modeling and simulation of adherence: approaches and applications in therapeutics.

Partial adherence with a prescribed or randomly assigned dose gives rise to unintended variability in actual drug exposure in clinical practice and during clinical trials. There are tremendous costs associated with incomplete and/or improper drug intake-to both individual patients and society as a whole. Methodology for quantifying the relation between adherence, exposure and drug response is an area of active research.

Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study.

Background: Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment.

Application and impact of population pharmacokinetics in the assessment of antiretroviral pharmacotherapy.

Population pharmacokinetics has been an important technique used to explore and define relevant sources of variation in drug exposure and response in patient populations. This has been especially true in the area of antiretroviral therapy where the assurance of adequate and sustained drug exposure of multiple agents is highly correlated with therapeutic success. Population pharmacokinetic analyses across the four drug classes and 20 US FDA-approved products used to treat HIV have been published to date.

Effects of ciprofloxacin on the stereoselective disposition of mexiletine in man.

Mexiletine is extensively metabolized in man, with less than 10% of the dose being excreted unchanged in urine. Clinical drug-drug interaction studies as well as in vitro drug metabolism studies suggest that CYP1A2, in addition to CYP2D6, is involved in the metabolism of mexiletine in man. Therefore, the objective of the study was to determine whether potential inhibition of CYP1A2 by the quinolone antibiotic agent ciprofloxacin would alter the stereoselective disposition of mexiletine.

Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: Adult AIDS Clinical Trial Group Study 398.

The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo.

Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacokinetics of amprenavir.

Objective: Pharmacokinetic interactions are expected when human immunodeficiency virus (HIV) protease inhibitors are coadministered because many are both substrates for and inhibitors of CYP3A4. The goal of this model-based pharmacokinetic analysis was to describe the differences observed in amprenavir pharmacokinetics among treatment arms in the Adult AIDS Clinical Trial Group (AACTG) study protocol 398 and to propose mechanisms to account for them.

Methods: One hundred seventy-six HIV-positive subjects receiving 1200 mg amprenavir twice daily as part of AACTG protocol 398 were included in the pharmacokinetic study.