Dose-fractionation studies of a phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria.

UCT594 is a 2-aminopyrazine carboxylic acid phosphatidylinositol 4-kinase inhibitor with potent asexual blood-stage activity, the potential for interrupting transmission, as well as liver-stage activities. Herein, we investigated pharmacokinetic/pharmacodynamic (PK/PD) relationships relative to blood-stage activity toward predicting the human dose. Dose-fractionation studies were conducted in the NSG mouse model to determine the PK/PD indices of UCT594, using the minimum parasiticidal concentration as a threshold.

hERG, Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole.

Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC = 0.0042 μM) and its derivatives, we designed and synthesized analogues based on compound ( NF54 IC = 0.012 μM; hERG IC = 0.

Population Pharmacokinetic Modeling and Dose Optimization of Acetaminophen and its Metabolites Following Intravenous Infusion in Critically ill Adults.

Background And Objective: Acetaminophen (paracetamol) is a ubiquitously administered drug in critically ill patients. Considering the dearth of literature, we evaluated the population pharmacokinetics of intravenous acetaminophen and its principal metabolites (sulfate and glucuronide) in this population.

Methods: Critically ill adults receiving intravenous acetaminophen were included in the study.

Integrating Pharmacokinetic-Pharmacodynamic Modeling and Physiologically Based Pharmacokinetic Modeling to Optimize Human Dose Predictions for Plasmodium falciparum Malaria: a Chloroquine Case Study.

The translation of a preclinical antimalarial drug development candidate to the clinical phases should be supported by rational human dose selection. A model-informed strategy based on preclinical data, which incorporates pharmacokinetic-pharmacodynamic (PK-PD) properties with physiologically based pharmacokinetic (PBPK) modeling, is proposed to optimally predict an efficacious human dose and dosage regimen for the treatment of Plasmodium falciparum malaria. The viability of this approach was explored using chloroquine, which has an extensive clinical history for malaria treatment.

Parental reporting of adverse drug reactions in South Africa: An online survey.

Background: The high incidence of adverse drug reactions (ADRs) in children is of global concern. Enhancing the reporting of ADRs could contribute to making safer medicines available to children.

Aim: To assess parents' awareness of reporting ADRs and their knowledge on the reporting procedures in South Africa.

Population pharmacokinetic-pharmacodynamic modeling of acetaminophen in preterm neonates with hemodynamically significant patent ductus arteriosus.

Background: Pharmacokinetics (PK) of intravenous acetaminophen has not been assessed in preterm neonates with hemodynamically significant patent ductus arteriosus (PDA). Moreover, there is a lack of data evaluating the association between PK and pharmacodynamics (PD) of acetaminophen in hemodynamically significant PDA. Hence, we performed a population PK-PD modeling of acetaminophen in preterm neonates with hemodynamically significant PDA.

Population Pharmacokinetics and Dose Optimization of Vancomycin in Critically Ill Children.

Background And Objective: Critically ill children may exhibit varied vancomycin pharmacokinetic parameters mainly due to altered protein binding, extracellular volume, and renal elimination. The objective of this study was to assess the pharmacokinetics of vancomycin in critically ill children and determine the optimum dose regimen.

Methods: This was a cross-sectional study of critically ill children admitted to a pediatric intensive care unit.

Ethionamide population pharmacokinetics/pharmacodynamics and therapeutic implications in South African adult patients with drug-resistant tuberculosis.

Introduction: Ethionamide is part of the drug-resistant tuberculosis regimen whose pharmacokinetic (PK) and pharmacodynamic (PD) information is limited. The aim of the study was to describe the PK and simulate doses to assess PD attainment.

Methods: This was an observational population PK study of patients admitted for drug-resistant tuberculosis at a hospital in South Africa.

Access to chronic medicines: patients' preferences for a last kilometre medicine delivery service in Cape Town, South Africa.

Background: Chronic patients are required to access their chronic medicines on a regular basis, often only to refill their repeat prescriptions. Adherence to chronic medicines is challenging and has stimulated health care providers to devise differentiated service delivery models of care to decentralise chronic medicine distribution to decrease the frequency of medicine collection at health care facilities. One such option includes a last kilometre medicine delivery service.

Assessment of Vancomycin Pharmacokinetics and Dose Regimen Optimisation in Preterm Neonates.

Background: The pharmacokinetics of vancomycin, a drug used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), varies between paediatric and adult patients.

Objective: The objective of this study was to assess the pharmacokinetics of vancomycin in preterm neonates and determine the optimum dose regimen.

Methods: This was a randomised double-blind study of preterm neonates admitted to neonatal intensive care units.

Amount of Cycloserine Emanating from Terizidone Metabolism and Relationship with Hepatic Function in Patients with Drug-Resistant Tuberculosis.

Background And Objectives: The dosing of cycloserine and terizidone is the same, as both drugs are considered equivalent or used interchangeably. Nevertheless, it is not certain from the literature that these drugs are interchangeable. Therefore, the amount of cycloserine resulting from the metabolism of terizidone and the relationship with hepatic function were determined.

Steady-state population pharmacokinetics of terizidone and its metabolite cycloserine in patients with drug-resistant tuberculosis.

Aims: Despite terizidone being part of the second-line recommended drugs for treatment of drug-resistant tuberculosis (DR-TB), information on its pharmacokinetics is scarce. The aim of this study was to describe the steady-state population pharmacokinetics (PPK) of terizidone and its primary metabolite cycloserine in patients with DR-TB and determine the effect of patient characteristics.

Methods: This clinical study involved 39 adult DR-TB patients admitted to Brewelskloof Hospital in Cape Town, South Africa for intensive treatment phase.

Sensitive Ultra-performance Liquid Chromatography Tandem Mass Spectrometry Method for Determination of Cycloserine in Plasma for a Pharmacokinetics Study.

A simple and sensitive ultra-performance liquid chromatography tandem mass spectrometry method has been developed and validated for the analysis of cycloserine in patients' plasma. Using methanol, cyloserine and propranolol (internal standard (IS)) was extracted from plasma by protein precipitation procedure. The chromatographic separation was successfully achieved on Phenomenex KinetexTM PFP C18 (2.

Population Pharmacokinetic Modelling of Pyrazinamide and Pyrazinoic Acid in Patients with Multi-Drug Resistant Tuberculosis.

Background And Objectives: Pyrazinamide, a drug used in the regimen for the treatment of drug-sensitive tuberculosis, is also used for the treatment of multidrug-resistant tuberculosis (MDR-TB). We aimed to describe the population pharmacokinetics of pyrazinamide and its major metabolite, pyrazinoic acid, in patients with MDR-TB and characterise the effects of demographic variables.

Methods: This was a non-randomised clinical study involving 51 adult patients admitted for the intensive phase of MDR-TB treatment.

Analysis of terizidone in plasma using HPLC-UV method and its application in a pharmacokinetic study of patients with drug-resistant tuberculosis.

A chromatographic method has been developed and validated for the first time for analysis of terizidone in plasma. Terizidone was extracted from plasma by protein precipitation using a mixture of acetonitrile and methanol (1:1, v/v). The chromatographic separation was achieved with a gradient of acetonitrile and water both containing 0.

Bone turnover markers in HIV-infected women on tenofovir-based antiretroviral therapy.

Background: Tenofovir disoproxil fumarate (TDF) antiretroviral therapy is associated with disruption of the bone turnover process.

Objectives: The objective of this study was to determine the association between tenofovir (TFV) plasma concentration and various bone turnover markers and compare these markers in HIV-infected women and HIV-uninfected controls.

Method: A cross-sectional sub-study included 30 HIV-infected women on TDF and 30 HIV-uninfected matched participants.

Associations between plasma tenofovir concentration and renal function markers in HIV-infected women.

Background: Tenofovir disoproxil fumarate (TDF) has been associated with kidney tubular dysfunction and reduced renal function. Limited studies were performed in Europe and Asia that related plasma tenofovir (TFV) concentration with renal function; no such studies to date have been performed on Africans.

Objective: To investigate the correlation between plasma tenofovir (TFV) concentration and certain renal function markers in HIV-infected women on TDF antiretroviral therapy (ART).