Integrated population pharmacokinetics of etirinotecan pegol and its four metabolites in cancer patients with solid tumors.

Purpose: Etirinotecan pegol (EP), a long-acting topoisomerase-1 inhibitor, is a polyethylene glycol conjugate of irinotecan, with an intended indication for treatment of breast cancer with brain metastases. The objective of this study was to develop a population pharmacokinetic (popPK) model of EP and four of its metabolites (irinotecan, SN38, SN38-glucuronide, and APC) and determine covariates affecting their pharmacokinetics.

Methods: Data from 83 cancer patients enrolled in phase 1 studies were used.

Population Pharmacokinetics of Boosted-Elvitegravir in HIV-Infected Patients.

Elvitegravir (EVG) is an HIV strand transfer integrase inhibitor approved for the treatment of HIV infection as a part of antiretroviral regimens containing cobicistat (COBI) or ritonavir (RTV) as a booster. The population pharmacokinetics of EVG in treatment-naive and -experienced HIV patients was determined, and the effects of demographic, biometric, and formulation covariates on EVG pharmacokinetics (PK) were evaluated. Data from 31 clinical studies (25 in healthy subjects, 6 phase 1b to phase 3 in HIV-1-infected patients) with COBI-boosted EVG studies (as EVG/co or EVG/COBI/FTC/TDF single-tablet regimen) or RTV-boosted EVG studies (EVG/r) were analyzed using NONMEM.

Pharmacokinetic analysis of 14C-ursodiol in newborn infants using accelerator mass spectrometry.

Pharmacokinetic studies in the neonatal population are often limited by the small volume of blood that can be collected. The high sensitivity of (14) C-accelerator mass spectrometry (AMS) enables pharmacokinetic studies to be conducted with greatly reduced sample volumes. We demonstrated the utility of AMS in infants by studying the plasma pharmacokinetic behavior of nanogram doses of (14) C-ursodiol administered as a non-perturbing microdose or as a microtracer with therapeutic doses of non-labeled ursodiol in infants.

Steady-state pharmacokinetics of gabapentin after administration of a novel gastroretentive extended-release formulation in postmenopausal women with vasomotor symptoms.

Background And Objective: Approximately 75% of postmenopausal women experience vasomotor symptoms (hot flashes). Currently, hormone replacement therapy is the only approved treatment for hot flashes. However, its use has been associated with an increased risk of invasive breast cancer, coronary heart disease, stroke and venous thromboembolic disease.

Drug discovery and development: lessons from an undeveloped drug.

In this article, drug discovery and preclinical development paradigms, as employed in today's pharmaceutical companies, are discussed. The antimalarial drug, artemisinin, is given as an example of a compound that is unlikely to be developed by a modern pharmaceutical company, yet is a safe and effective drug for the treatment of a deadly disease. It is argued that the use of prespecified charts, listing undesired properties to deselect molecules may lead to missed opportunities in bringing best-in-class medications to patients.

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview.

Glumetz (Depomed, Inc., Menlo Park, CA, USA) is a recently approved gastric retentive extended-release formulation of metformin (M-ER) that provides effective, sustained and well-tolerated glycemic control with once daily administration. Pharmacokinetic studies have demonstrated a similar bioavailability of M-ER administered once daily to immediate-release metformin given twice daily.

Pharmacokinetics of gabapentin after a single day and at steady state following the administration of gastric-retentive- extended-release and immediate-release tablets: a randomized, open-label, multiple-dose, three-way crossover, exploratory study in healthy subjects.

Background: Gabapentin absorption is mediated by a saturable transporter system located in the upper gastrointestinal tract, indicating a short window of absorption. Therefore, conventional sustained formulations would likely result in decreased bioavailability, as the dosage form would pass through the window of absorption before the drug could be completely released.

Objective: The aim of this study was to compare the pharmacokinetics of an oral, gastric-retentive, gabapentin extended-release (G-ER) formulation with a gabapentin immediate-release (G-IR) formulation after single and multiple daily doses in healthy subjects.

Population pharmacokinetics of chloroquine and sulfadoxine and treatment response in children with malaria: suggestions for an improved dose regimen.

What Is Already Known About This Subject: * Both chloroquine (CQ) and sulfadoxine/ pyrimethamine (SDx/PYR) remain important drugs in the control of malaria. * The available data on CQ, SDx and PYR are summary pharmacokinetic parameters based on classical/traditional methods, mostly in adults. * No study has described the population pharmacokinetics of a fixed-dose CQ + SDx/PYR combination in children with falciparum malaria.

Regadenoson, a selective A2A adenosine receptor agonist, causes dose-dependent increases in coronary blood flow velocity in humans.

Background: Regadenoson is a selective A2A adenosine receptor agonist and vasodilator used to increase the heterogeneity of distribution of coronary blood flow during myocardial perfusion imaging. This study characterized the dose dependence of regadenoson-induced coronary hyperemia.

Methods And Results: An open-label, dose-escalation study of regadenoson (10-500 microg, rapid intravenous bolus) was performed in 34 subjects; in 4 additional subjects, the effect of aminophylline to reverse the response to regadenoson was determined.

Regadenoson pharmacokinetics and tolerability in subjects with impaired renal function.

The authors have investigated the pharmacokinetics and tolerability of regadenoson, a selective A2A adenosine receptor agonist for use in drug-stressed myocardial perfusion imaging in subjects with varying degrees of renal function. Sixteen subjects with different creatinine clearance values (range: 15-132 mL/min) received a single intravenous bolus dose of 400 microg regadenoson. A population pharmacokinetic model was developed to describe the pharmacokinetics of regadenoson in these subjects.

Retrospective analysis of artemisinin pharmacokinetics: application of a semiphysiological autoinduction model.

Aims: To describe the time-course of the autoinduction of artemisinin by applying a semi-physiological pharmacokinetic model.

Methods: Plasma concentration-time data from six clinical studies involving oral administration of artemisinin to healthy subjects and malaria patients were included in the analysis. NONMEM was used to apply a semi-physiological model incorporating metabolizing enzymes and a pharmacokinetic model including a separate hepatic compartment.

A population pharmacokinetic/pharmacodynamic analysis of regadenoson, an adenosine A2A-receptor agonist, in healthy male volunteers.

Objectives: The aims of this study were to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of regadenoson (CVT-3146) in healthy, male volunteers.

Methods: Thirty-six healthy, male volunteers aged 18-50 years were included in this randomised, double-blind, crossover, placebo-controlled study to evaluate single intravenous bolus doses of regadenoson that ranged from 0.1 to 30.

Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of artemisinin.

Purpose: To characterize artemisinin pharmacokinetics (PK) and its antimalarial activity in vivo.

Methods: Artemisinin salivary concentration and parasite count data were obtained from Vietnamese malaria patients receiving two different dosage regimens. PK data were analysed using a previously developed semiphysiological model incorporating autoinduction of eliminating enzymes.

A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction.

Aims: Previous studies have shown that the antimalarial drug artemisinin is a potent inducer of its own metabolism in both patients and healthy subjects. The aim of this study was to characterize the time-dependent pharmacokinetics of artemisinin in healthy subjects.

Methods: Twenty-four healthy males were randomized to receive either a daily single dose of 500 mg oral artemisinin for 5 days, or single oral doses of 100/100/250/250/500 mg on each of the first 5 days.

Simple solution to a common statistical problem: interpreting multiple tests.

Background: The misinterpretation of the results of multiple statistical tests is an error commonly made in scientific literature. When testing several outcome variables simultaneously, many researchers declare a statistically significant result for each test having a P value of <0.05, for example.

Artemisinin derivatives: toxic for laboratory animals, safe for humans?

A discrepancy seems to prevail with regard to the toxicity and safety of the artemisinin family of antimalarials. While these compounds have been found to be virtually void of any serious side effects in humans, their neurotoxicity in animal models has raised concerns about their use. In this paper, we present selected examples of both pre-clinical and clinical studies dealing with adverse effects of artemisinin drugs.

The pharmacokinetics of linezolid are not affected by concomitant intake of the antioxidant vitamins C and E.

In vitro metabolism experiments have suggested a possible role for endogenous reactive oxygen species (ROS) in the in vivo clearance of linezolid, a synthetic antibiotic of the oxazolidinone class. This observation has resulted in the hypothesis that dietary antioxidant supplements might disturb the balance of ROS in vivo and thereby lower the clearance of linezolid. The purpose of this open-label, two-group parallel design study was to investigate whether continuous intake of widely used vitamin C or vitamin E will affect the pharmacokinetics of linezolid.

Artemisinin pharmacokinetics and efficacy in uncomplicated-malaria patients treated with two different dosage regimens.

The immediate efficacies of two oral dosage regimens of artemisinin were investigated in 77 male and female adult Vietnamese falciparum malaria patients randomly assigned to treatment with either 500 mg of artemisinin daily for 5 days (group A; n = 40) or artemisinin at a dose of 100 mg per day for 2 days, with the dose increased to 250 mg per day for 2 consecutive days and with a final dose of 500 mg on the fifth day (group B; n = 37). Parasitemia was monitored every 4 h. The average parasite clearance time was longer in group B than in group A (means +/- standard deviations, 50 +/- 23 and 34 +/- 14 h, respectively; P < 0.