pyDarwin machine learning algorithms application and comparison in nonlinear mixed-effect model selection and optimization.

Forward addition/backward elimination (FABE) has been the standard for population pharmacokinetic model selection (PPK) since NONMEM® was introduced. We investigated five machine learning (ML) algorithms (Genetic algorithm [GA], Gaussian process [GP], random forest [RF], gradient boosted random tree [GBRT], and particle swarm optimization [PSO]) as alternatives to FABE. These algorithms were applied to PPK model selection with a focus on comparing the efficiency and robustness of each of them.

RPEM: Randomized Monte Carlo parametric expectation maximization algorithm.

Inspired from quantum Monte Carlo, by sampling discrete and continuous variables at the same time using the Metropolis-Hastings algorithm, we present a novel, fast, and accurate high performance Monte Carlo Parametric Expectation Maximization (MCPEM) algorithm. We named it Randomized Parametric Expectation Maximization (RPEM). We compared RPEM with NONMEM's Importance Sampling Method (IMP), Monolix's Stochastic Approximation Expectation Maximization (SAEM), and Certara's Quasi-Random Parametric Expectation Maximization (QRPEM) for a realistic two-compartment voriconazole model with ordinary differential equations using simulated data.

pyDarwin: A Machine Learning Enhanced Automated Nonlinear Mixed-Effect Model Selection Toolbox.

pyDarwin is an open-source Python package for nonlinear mixed-effect model selection. pyDarwin combines machine-learning algorithms and NONMEM to perform a global search for the optimal model in a user-defined model search space. Compared with traditional stepwise search, pyDarwin provides an efficient platform for conducting an objective, robust, less labor-intensive model selection process without compromising model interpretability.

Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans.

Background: Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells.

A Regression Approach to Visual Predictive Checks for Population Pharmacometric Models.

A visual predictive check (VPC) is a common diagnostic procedure for population pharmacometric models. Typically, VPCs are generated by specifying intervals, or "bins", of an independent variable (e.g.

Interdisciplinary pharmacometrics linking oseltamivir pharmacology, influenza epidemiology and health economics to inform antiviral use in pandemics.

Aims: A modular interdisciplinary platform was developed to investigate the economic impact of oseltamivir treatment by dosage regimen under simulated influenza pandemic scenarios.

Methods: The pharmacology module consisted of a pharmacokinetic distribution of oseltamivir carboxylate daily area under the concentration-time curve at steady state (simulated for 75 mg and 150 mg twice daily regimens for 5 days) and a pharmacodynamic distribution of viral shedding duration obtained from phase II influenza inoculation data. The epidemiological module comprised a susceptible, exposed, infected, recovered (SEIR) model to which drug effect on the basic reproductive number (R ), a measure of transmissibility, was linked by reduction of viral shedding duration.

Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects.

1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor. 2.

Comparative benefit of malaria chemoprophylaxis modelled in United Kingdom travellers.

Background: Chemoprophylaxis against falciparum malaria is recommended for travellers from non-endemic countries to malarious destinations, but debate continues on benefit, especially with regard to mefloquine. Quantification of benefit for travellers from the United Kingdom (UK) was modelled to assist clinical and public health decision making.

Methods: The model was constructed utilising: World Tourism Organization data showing total number of arrivals from the UK in countries with moderate or high malaria risk; data from a retrospective UK Clinical Practice Research Datalink (CPRD) drug utilisation study; additional information on chemoprophylaxis, case fatality and tolerability were derived from the travel medicine literature.

Safety and pharmacokinetics of daclizumab in pediatric renal transplant recipients.

This study examined the safety and pharmacokinetics/pharmacodynamics of daclizumab in combination with mycophenolate mofetil (or azathioprine), corticosteroids, and cyclosporine or tacrolimus, in 61 pediatric renal allograft recipients in three age groups: less than or equal to five yr (n = 18), 6-12 yr (n = 18), and 13-17 yr (n = 25). The dosing regimen was daclizumab 1.0 mg/kg before transplantation, followed by four biweekly doses.

Population pharmacokinetics and exposure-response relationship of enfuvirtide in treatment-experienced human immunodeficiency virus type 1-infected patients.

Objective: Our objective was to characterize population pharmacokinetics of enfuvirtide, 90 mg twice daily injected subcutaneously, in treatment-experienced human immunodeficiency virus type 1 (HIV-1)-infected patients, as well as the relationship between exposure and antiviral effect.

Methods: Plasma concentrations of enfuvirtide and HIV-1 ribonucleic acid were obtained from 628 patients in 2 phase III studies. NONMEM software was used for population pharmacokinetic analysis and to assess the effects of age, gender, body weight, anti-gp41 antibodies, and concomitant drugs.

Pharmacokinetics, pharmacodynamics and drug interaction potential of enfuvirtide.

Enfuvirtide, the first fusion inhibitor approved for the treatment of HIV-1 infection, is a synthetic peptide that binds to HIV-1 glycoprotein 41, blocking the fusion of viral and cellular membranes. When administered subcutaneously at the recommended dose of 90 mg twice daily with optimised background antiretroviral therapy, enfuvirtide significantly reduces plasma HIV-1 RNA levels up to 48 weeks compared with optimised background therapy alone. Enfuvirtide exhibits a small volume of distribution (5.

Pharmacokinetics of enfuvirtide in a patient with impaired renal function.

Enfuvirtide is the first member of the fourth class of antiretroviral drugs to become available. We present a case report of a human immunodeficiency virus (HIV)-positive patient with mild renal impairment who developed severe renal impairment secondary to tenofovir therapy while receiving enfuvirtide. Because the patient's pharmacokinetic profile was not significantly altered, compared with that of HIV-infected patients with normal renal function, no dose modifications were required.

Pharmacokinetics of daclizumab and mycophenolate mofetil with cyclosporine and steroids in renal transplantation.

Daclizumab and mycophenolate mofetil (MMF) decrease the incidence of acute allograft rejection. This double-blind, randomized, placebo-controlled trial was performed primarily to assess the pharmacokinetics of MMF in an immunosuppressive regimen incorporating daclizumab. At five centers, 75 renal transplant recipients were randomized 2:1 to receive either daclizumab 1 mg/kg or placebo pre-transplantation and every other week, for a total of five doses.

Lack of enzyme-inducing effect of rifampicin on the pharmacokinetics of enfuvirtide.

The primary objective was to determine whether rifampicin influences the pharmacokinetics of enfuvirtide in HIV-1-infected patients. In a single-center, open-label, one-sequence crossover, clinical pharmacology study, 12 HIV-1-infected adults received enfuvirtide (90 mg, twice daily) on days 1 to 3 and days 11 to 13 (morning dose only on days 3 and 13) and rifampicin (600 mg, once daily) from days 4 to 13. Plasma concentrations were measured for enfuvirtide and its metabolite (days 3 and 13) and rifampicin (day 13 only).

Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition.

Objective: Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies.

Methods: Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion.