Confirming the Suitability of a Gentamicin Dosing Strategy in Neonates Using the Population Pharmacokinetic Approach with Truncated Sampling Duration.

(1) Background: Gentamicin is known to be nephrotoxic and ototoxic. Although gentamicin dosage guidelines have been established for preterm and term neonates, reports do show attainment of recommended peak concentrations but toxic gentamicin concentrations are common in this age group. (2) Methods: This was a prospective, observational study conducted in Namibia with 52 neonates.

Predictors of gentamicin therapy failure in neonates with sepsis.

Sepsis is a common disease with high morbidity and mortality among newborns in intensive care units world-wide. Gram-negative bacillary bacteria are the major source of infection in neonates. Gentamicin is the most widely used aminoglycoside antibiotic in empiric therapy against early-onset sepsis.

Population-Based Characterization of the Pharmacokinetics and Food Effect of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer Disease.

Pharmacokinetic (PK) data from 28 subjects who received 5-200-mg single ascending doses of ANAVEX3-71, formerly AF710B, were analyzed to characterize the PK of ANAVEX3-71 and its M8 metabolite. PK data from 12 subjects who received 160 mg ANAVEX3-71 under fed and fasted conditions were analyzed to characterize the effect of food on the PK of the drug and its M8 metabolite. PK was characterized using the standard 2-stage approach and the nonlinear mixed-effects modeling approach.

A mechanistic assessment of the nature of pharmacodynamic drug-drug interaction in vivo and in vitro.

Combination pharmacotherapy is becoming increasingly necessary because most diseases are pathophysiologically controlled at the subcellular level by target proteins in a combinatorial manner. We demonstrate the application of the stimulus-response mechanistic model in characterising the drug and physiological properties of pharmacodynamic drug-drug interactions (PDDI) using previously published in vitro and in vivo drug combination experiments. The in vitro experiment tested the effect of a combination of SCH66336 and 4-HPR on the survival of in squamous cell carcinoma cell lines, while the in vivo experiment tested the effect of a combination of cetuximab and cisplatin on tumour growth inhibition in female xenograft mice.

The new big is small: Leveraging knowledge from small trials for rare disease drug development: Blarcamesine for Rett syndrome.

Big data in drug development may not satisfactorily address the demands of precision medicine in a rare disease population, making the use of smaller clinical trials necessary. Consequently, the use of innovative design and analysis of these clinical trials using model-informed approaches have become indispensable. This requires informative exposure-outcome analysis, together with formal statistical analysis, which should include the strength of evidence for a study outcome.

Plasma concentration and eGFR in preterm and term neonates receiving gentamicin or successive amikacin therapy.

Background: Gentamicin and amikacin are aminoglycoside antibiotics which are renally excreted and known to be nephrotoxic. Estimate of glomerular filtration rate (eGFR) per body surface area is lower in neonates than in adults and exposure to these drugs could lead to more suppression in kidney function. The aim of this study was to determine maximum and minimum plasma concentrations (C and C), time to reach C levels of gentamicin and amikacin, and to assess eGFR in preterm and term neonates.

Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Chemotherapy-Induced Neutropenia in Adults With Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

Importance: Plinabulin is a novel, non-granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects.

Objective: To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non-small lung cancer.

Design, Setting, And Participants: This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine.

Maximizing Knowledge Extraction From Patient-Reported Outcome Data Using Exposure-Outcome Item Response Modeling Approach: Understanding Efavirenz-Induced Central Nervous System Toxicity.

This investigation was undertaken to maximally extract hidden knowledge from an efavirenz-based trial data set using an item response theory-based approach to exposure-outcome analysis. The aim was to understand the influence of efavirenz exposure on the underlying neuropsychiatric impairment in HIV/AIDS patients. Data from 196 individuals with 4136 neuropsychiatric impairment symptom observations at baseline and 2 and 12 weeks of 600-mg efavirenz-based therapy was analyzed.

Pharmacometrics of clobazam in pediatrics: Prediction of effective clobazam doses for Dravet syndrome.

Objective: To describe the use of a population pharmacokinetic (PopPK) model incorporating weight and ontogeny to identify effective clobazam (CLB) dosing for use in a clinical trial in pediatric patients with Dravet syndrome.

Methods: Pharmacokinetic data were combined from 3 CLB trials (OV-1012, OV-1017, and study 301) and a simulated study (study 401) for a total of 1306 CLB and 1305 N-desmethyl clobazam (N-CLB) samples from 193 Lennox-Gastaut syndrome patients and healthy subjects aged 6 months to 45 years. A structured approach based on US Food and Drug Administration guidance and pharmacometric knowledge discovery was developed using a nonlinear mixed-effects approach.

Clinical Proof-of-concept of a Novel Platform Utilizing Biopsy-derived Live Single Cells, Phenotypic Biomarkers, and Machine Learning Toward a Precision Risk Stratification Test for Prostate Cancer Grade Groups 1 and 2 (Gleason 3 + 3 and 3 + 4).

Objective: To examine the ability of a novel live primary-cell phenotypic (LPCP) test to predict postsurgical adverse pathology (P-SAP) features and risk stratify patients based on SAP features in a blinded study utilizing radical prostatectomy (RP) surgical specimens.

Methods: Two hundred fifty-one men undergoing RP were enrolled in a prospective, multicenter (10), and proof-of-concept study in the United States. Fresh prostate samples were taken from known areas of cancer in the operating room immediately after RP.

Predictors of tuberculosis treatment success under the DOTS program in Namibia.

Objectives: Optimal treatment success rates are critical to end tuberculosis in Namibia. Despite the scale-up of high quality directly observed therapy short-course strategy (DOTS) in Namibia, treatment success falls short of the global target of 90%. The objective of this study was to ascertain the predictors of treatment success rates under DOTS in Namibia to provide future direction.

Transition modeling of neuropsychiatric impairment in HIV.

Few studies have reported analyses of neuropsychiatric impairment (NPI) data from HIV patients, in a real world clinical setting with the aim of establishing association between anti-retroviral drug concentrations and NPI development and resolution. No study has modeled the effect of efavirenz exposure beyond the pre-steady state period on the frequency and duration of NPI. The data used consists of 196 HIV patients whose efavirenz pharmacokinetic parameters were previously determined.

Drug-metabolism mechanism: Knowledge-based population pharmacokinetic approach for characterizing clobazam drug-drug interactions.

A metabolic mechanism-based characterization of antiepileptic drug-drug interactions (DDIs) with clobazam in patients with Lennox-Gastaut syndrome (LGS) was performed using a population pharmacokinetic (PPK) approach. To characterize potential DDIs with clobazam, pharmacokinetic (PK) data from 153 patients with LGS in study OV-1012 (NCT00518713) and 18 healthy participants in bioavailability study OV-1017 were pooled. Antiepileptic drugs (AEDs) were grouped based on their effects on the cytochrome P450 (CYP) isozymes responsible for the metabolism of clobazam and its metabolite, N-desmethylclobazam (N-CLB): CYP3A inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), or CYP2C19 inhibitors (felbamate, oxcarbazepine).

An integrative population pharmacokinetics approach to the characterization of the effect of hepatic impairment on clobazam pharmacokinetics.

An integrative population pharmacokinetics (PPK)-based approach was used to characterize the effect of hepatic impairment on clobazam PK and its major metabolite in systemic circulation, N-desmethylclobazam (N-CLB). At therapeutic clobazam dosages, N-CLB plasma concentrations are 3-5 times greater than the parent compound. PK data from clinical trials in patients with Lennox-Gastaut syndrome (LGS; OV-1002 and OV-1012), healthy participants (OV-1016), and participants with and without renal impairment (OV-1032), as well as those from a publication describing the effects of hepatic impairment on clobazam PK, were merged to create the PPK model.

Markov model for characterizing neuropsychologic impairment and Monte Carlo simulation for optimizing efavirenz therapy.

The study was undertaken to develop a pharmacokinetic-pharmacodynamic model to characterize efavirenz-induced neuropsychologic impairment, given preexistent impairment, which can be used for the optimization of efavirenz therapy via Monte Carlo simulations. The modeling was performed with NONMEM 7.2.

The future of drug development: advancing clinical trial design.

Declining pharmaceutical industry productivity is well recognized by drug developers, regulatory authorities and patient groups. A key part of the problem is that clinical studies are increasingly expensive, driven by the rising costs of conducting Phase II and III trials. It is therefore crucial to ensure that these phases of drug development are conducted more efficiently and cost-effectively, and that attrition rates are reduced.

A pragmatic approach to the design of population pharmacokinetic studies.

The publication of a seminal article on nonlinear mixed-effect modeling led to a revolution in pharmacokinetics (PKs) with the introduction of the population approach. Since then, interest in obtaining accurate and precise estimates of population PK parameters has led to work on population PK study design that extended previous work on optimal sampling designs for individual PK parameter estimation. The issues and developments in the design of population PK studies are reviewed as a prelude to investigating, via simulation, the performance of 2 approaches (population Fisher information matrix D-optimal design and informative block [profile] randomized [IBR] design) for designing population PK studies.

A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-alpha in previously untreated patients with chronic hepatitis C.

Inhibition of inosine monophosphate dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin (RBV), a critical component of the current treatment for chronic hepatitis C (CHC). This study was a double-blind, placebo-controlled dose-escalation study of a novel, selective, orally active small molecule inhibitor of IMPDH, merimepodib (VX-497 or MMPD) in combination with standard interferon-alpha (IFN-alpha). Fifty-four treatment-naive patients with genotype-1 CHC were randomized to receive IFN-alpha 3 MIU subcutaneously three times a week, alone or in combination with 100 mg or 300 mg (every 8 h) of MMPD for 4 weeks.

A random sampling approach for robust estimation of tissue-to-plasma ratio from extremely sparse data.

his study was performed to develop a new nonparametric approach for the estimation of robust tissue-to-plasma ratio from extremely sparsely sampled paired data (ie, one sample each from plasma and tissue per subject). Tissue-to-plasma ratio was estimated from paired/unpaired experimental data using independent time points approach, area under the curve (AUC) values calculated with the naïve data averaging approach, and AUC values calculated using sampling based approaches (eg, the pseudoprofile-based bootstrap [PpbB] approach and the random sampling approach [our proposed approach]). The random sampling approach involves the use of a 2-phase algorithm.

Data supplementation: a pharmacokinetic/pharmacodynamic knowledge creation approach for characterizing an unexplored region of the response surface.

Purpose: To develop a data supplementation [i.e., a pharmacokinetic/pharmacodynamics (PK/PD) knowledge creation] approach for generating supplemental data to be used in characterizing a targeted unexplored segment of the response surface.

Population pharmacokinetics III: design, analysis, and application of population pharmacokinetic Studies.

Objective: To present a framework within which population pharmacokinetic (PPK) studies should be designed and analyzed and discuss the application of developed PPK models.

Methods: Information on PPK was retrieved from a MEDLINE search (1979-December 2003) of the literature and a bibliographic evaluation of review articles and books. This information is used in conjunction with experience to explain the design and analysis of PPK studies.

Population pharmacokinetics II: estimation methods.

Objective: To present, compare, and contrast the various approaches to estimating population pharmacokinetic (PPK) models with respect to the mathematical foundation, statistical aspects, software programs for implementation, and underlying assumptions.

Data Sources: Information on PPK was retrieved from a MEDLINE search (1977-August 2004) of literature and a bibliographic review of review articles and books. This information is used in conjunction with experience to explain the various methodologic approaches to PPK.

Population pharmacokinetics I: background, concepts, and models.

Objective: To present and emphasize the background, foundations, utility, and conceptual underlying theory of the population pharmacokinetic (PPK) approach with an examination of the advantages when compared with other approaches of pharmacokinetic modeling.

Data Sources: Information on PPK was retrieved from a MEDLINE search (1979-June 2002) of literature and a bibliographic review of review articles and books.

Study Selection And Data Extraction: All articles identified from data sources were evaluated and relevant information was included in this review.

Model appropriateness and population pharmacokinetic modeling.

The purpose of this study was to define model appropriateness, identifying the individual elements thereof, and to set out a framework within which model appropriateness could be determined for population pharmacokinetic (PPK) models. Model appropriateness was defined by stating the problem to be solved, with the intended use of the model being the pivotal event. The elements of model appropriateness were identified with the type of model (descriptive vs.