Pharmacokinetics and safety of TBAJ-876, a novel antimycobacterial diarylquinoline, in healthy subjects.

TBAJ-876, a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile compared with bedaquiline, is under development for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). A phase 1, first-in-human study of TBAJ-876, comprising a single-ascending dose (SAD) part including a food effect cohort, a multiple-ascending dose (MAD) part, and a relative bioavailability part of tablets versus oral suspension, was conducted on 137 healthy adults. A drug-drug interaction study was conducted on 28 healthy adults to evaluate the effects of TBAJ-876 on a cytochrome P450 3A4 substrate (midazolam) and a P-glycoprotein substrate (digoxin).

Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling.

Background And Introduction: The dispersible tablet formulation (DTF) of pretomanid has been developed to facilitate future use in children. This work aimed to assess the pharmacokinetics (PK) and relative bioavailability of the DTF compared to the marketed formulation (MF) and the potential influence of dose.

Methods: Pretomanid DTF was investigated in a single-dose, randomized, four-period, cross-over study, with 7 days of washout between doses.

Male reproductive hormones in patients treated with pretomanid.

Pretomanid (Pa) is a nitroimidazole-class drug recently approved by the US Food and Drug Administration and other regulatory authorities as part of a regimen for treating highly drug-resistant pulmonary infections. Studies in rodents identified the testis as a target organ of concern, which led to monitoring of reproductive hormones in >800 male patients enrolled in four clinical trials of Pa-containing regimens and the HRZE (isoniazid+rifampin+pyrazinamide+ethambutol) control regimen. Serum hormone levels relevant to male reproductive health - follicle stimulating hormone (FSH), luteinizing hormone (LH), inhibin B (InhB) and total testosterone (T) - from the four clinical trials were summarized numerically and analyzed by repeated-measures modeling.

Single Ascending-Dose Study To Evaluate the Safety, Tolerability, and Pharmacokinetics of Sutezolid in Healthy Adult Subjects.

The primary objective of the study was to evaluate the safety and tolerability of single oral doses of sutezolid tablets administered under fasting conditions in healthy adult subjects. The secondary objective was to determine the pharmacokinetics (PK) of sutezolid and two metabolites, PNU-101603 and PNU-101244. Overall, sutezolid was well tolerated when administered as a 300-mg, 600-mg, 1,200-mg, or 1,800-mg dose in healthy adult subjects under fasting conditions.

Proposed Linezolid Dosing Strategies to Minimize Adverse Events for Treatment of Extensively Drug-Resistant Tuberculosis.

Background: We evaluated Nix-TB trial data (NCT02333799, N = 109) to provide dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis. .

Methods: A pharmacokinetic model and toxicodynamic models for peripheral neuropathy, hemoglobin, and platelets were developed.

Phase 1 Study of the Effects of the Tuberculosis Treatment Pretomanid, Alone and in Combination With Moxifloxacin, on the QTc Interval in Healthy Volunteers.

Tuberculosis (TB) continues to be a serious threat to public health throughout the world. Newer treatments are needed that could offer simplified regimens with activity against both drug-sensitive and drug-resistant bacilli, while optimizing safety. Pretomanid (PA-824), a nitroimidazooxazine compound, is a new drug for the treatment of pulmonary TB that was recently approved in the United States and Europe in the context of a regimen combined with bedaquiline and linezolid.

An Exposure-Response Perspective on the Clinical Dose of Pretomanid.

Pretomanid was approved by the U.S. FDA, via the limited population pathway for antibacterial and antifungal drugs, as part of a three-drug regimen with bedaquiline and linezolid for the treatment of extensively drug-resistant and treatment-intolerant or nonresponsive multidrug-resistant tuberculosis.

Fourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary Tuberculosis.

Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. From November 2014 to November 2016, we randomized 114 drug-sensitive treatment-naive pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid at 300 mg once daily (QD), 300 mg twice daily (BD), 600 mg QD, 600 mg BD, 1,200 mg QD, 1,200 mg three times per week (TIW), or a combination of isoniazid, rifampin, pyrazinamide, and ethambutol. Sixteen-hour sputum samples were collected overnight, and bactericidal activity was characterized by the daily percentage change in time to positivity (TTP) and the daily rate of change in log(CFU).

Daily Dosing for Bedaquiline in Patients with Tuberculosis.

The bedaquiline regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) in adults is a loading dose of 400 mg QD for 2 weeks followed by 200 mg thrice weekly (TIW) for 22 weeks. Most TB antibiotics administered with bedaquiline are given QD. Using pharmacokinetic simulations, we explored alternative QD bedaquiline regimens and determined that 200 mg QD for 8 weeks followed by 100 mg QD provides comparable exposures to the approved regimen.

Population Pharmacokinetics of the Antituberculosis Agent Pretomanid.

A population pharmacokinetic (PopPK) model for pretomanid was developed using data from 14 studies in the pretomanid development program: six phase 1 studies, six phase 2 studies, and two phase 3 studies. The final analysis data set contained 17,725 observations from 1,054 subjects, including healthy subjects and subjects with drug-sensitive, multidrug-resistant, or extensively drug-resistant pulmonary tuberculosis dosed pretomanid in monotherapy or combination therapy for up to 6 months. Pretomanid pharmacokinetic behavior was described by a one-compartment model that at a given dose was linear in its absorption and clearance processes but where the rate of absorption and extent of bioavailability changed with dose.

Long-Term Effects on QT Prolongation of Pretomanid Alone and in Combinations in Patients with Tuberculosis.

Concentration-QTc modeling was applied to pretomanid, a new nitroimidazooxazine antituberculosis drug. Data came from eight phase 2 and phase 3 studies. Besides pretomanid alone, various combinations with bedaquiline, linezolid, moxifloxacin, and pyrazinamide were considered; special attention was given to the bedaquiline-pretomanid-linezolid (BPaL) regimen that has demonstrated efficacy in the Nix-TB study in subjects with extensively drug-resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis.

Population pharmacokinetics-pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex.

Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5-15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance.

Population Pharmacokinetics of Subcutaneous Pasireotide in Healthy Volunteers and Cushing's Disease Patients.

Background And Objective: Pasireotide (SOM230, Signifor) is a somatostatin analog approved in a subcutaneous formulation for the treatment of Cushing's disease. This analysis characterizes the population pharmacokinetics (PopPK) of subcutaneous pasireotide jointly in healthy volunteers (HVs) and Cushing's disease patients (CDPs), evaluating the effects of age, body size, and population on pasireotide pharmacokinetics.

Methods: The analysis dataset included five phase I studies and one each from phase II and phase III.

Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors.

Purpose: Sonidegib (Odomzo) selectively inhibits smoothened and suppresses the growth of hedgehog pathway-dependent tumors. A population pharmacokinetic (PK) analysis of sonidegib in healthy subjects and patients with advanced solid tumors was conducted to characterize PK, determine variability, and estimate covariate effects.

Methods: PK data from five phase 1 or 2 studies (N = 436) in the dose range from 100 to 3000 mg were analyzed using NONMEM.

Population pharmacokinetics of intravenous and oral panobinostat in patients with hematologic and solid tumors.

Purpose: The study aimed to characterize the population pharmacokinetics of panobinostat, a pan-deacetylase inhibitor that has demonstrated efficacy in combination with bortezomib and dexamethasone in patients with multiple myeloma.

Methods: A nonlinear mixed-effect model was used to fit plasma panobinostat concentration-time data collected from patients across 14 phase 1 and phase 2 trials following either oral or intravenous (IV) administration. The model was used to estimate bioavailabilities of the two oral formulations and the effects of demographic and clinical covariates on the central volume of distribution and clearance of panobinostat.

Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis.

Background: Relationships between improvements in lung function and other clinical outcomes in chronic obstructive pulmonary disease (COPD) are not documented extensively. We examined whether changes in trough forced expiratory volume in 1 second (FEV(1)) are correlated with changes in patient-reported outcomes.

Methods: Pooled data from three indacaterol studies (n = 3313) were analysed.

A therapeutic drug monitoring algorithm for refining the imatinib trough level obtained at different sampling times.

Background: Correlation analyses have demonstrated that maintaining an adequate imatinib (IM) trough concentration would be important for clinical response in patients with chronic myeloid leukemia (CML) and Kit-positive gastrointestinal stromal tumors. The objectives of the current work were to use a pharmacokinetic model to refine the trough levels obtained at different sampling times and to propose a therapeutic drug monitoring algorithm and an acceptable sampling time window for imatinib trough sampling.

Methods: The pharmacokinetics of IM in patients (pts) with CML were characterized based on historical data from a Phase III study.

Diagnostics for confounding in PK/PD models for oxcarbazepine.

One type of pharmacokinetic/pharmacodynamic (PK/PD) relationship that is used to characterize the therapeutic action of a drug is the relationship between some univariate summary of the plasma-concentration-versus-time profile and the drug effect on a response outcome. Operationally, such a relationship may be observed in a large clinical trial where randomly sampled patients are randomized to different values of the concentration summary. If, under such conditions, the relationship between concentration and effect does not depend on the dose needed to attain the target concentration, such a relationship will be called a true PK/PD relationship.

On some "disadvantages" of the population approach.

In a seminal article on population pharmacokinetic modeling, researchers demonstrated how means and variances of pharmacokinetic parameters for a patient population could be inferred from sparse data collected under conditions of routine patient care. But they also identified 4 potential concerns about their methodology: unobserved confounding variables may bias the inferences; conditions under which data are collected may lead to inaccuracies of reporting or recording; correlations among important predictor variables may reduce statistical efficiency; and costs cannot be controlled by principles of study design. Experiences are reviewed that relate to these potential disadvantages.

Pharmacokinetic-pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly.

Objective: Acromegaly is a serious hormonal disorder resulting from a pituitary adenoma causing excess growth hormone (GH) production. Somatostatin analogs such as octreotide have been the medical treatment of choice. SOM230, a novel somatostatin analog, was compared with octreotide with respect to pharmacokinetic (PK) profiles and inhibition of GH secretion in acromegalic patients.

Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients.

FTY720, a new and potent immunosuppressant, causes in animal models a rapid, reversible reduction of all subsets of peripheral blood lymphocytes, inducing their migration to secondary lymphoid organs. In this human phase I trial, the pharmacodynamics of single oral doses of FTY720 were evaluated. A randomized, double-blind, placebo-controlled, time-lagged study of six different single ascending oral doses of FTY720 ranging from 0.

Bias in the Wagner-Nelson estimate of the fraction of drug absorbed.

Purpose: To examine and quantify bias in the Wagner-Nelson estimate of the fraction of drug absorbed resulting from the estimation error of the elimination rate constant (k), measurement error of the drug concentration, and the truncation error in the area under the curve.

Methods: Bias in the Wagner-Nelson estimate was derived as a function of post-dosing time (t), k, ratio of absorption rate constant to k (r), and the coefficient of variation for estimates of k (CVk), or CV% for the observed concentration, by assuming a one-compartment model and using an independent estimate of k. The derived functions were used for evaluating the bias with r = 0.

Mealtime glucose regulation with nateglinide in healthy volunteers: comparison with repaglinide and placebo.

Objective: This study was designed to compare the pharmacodynamic effects of single doses of nateglinide (A-4166), repaglinide, and placebo on mealtime insulin secretion and glycemic control in healthy subjects.

Research Design And Methods: Fifteen healthy volunteers participated in this open-label five-period crossover study. They received single 10-min preprandial doses of 120 mg nateglinide, 0.