Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients

Abstract

Pretomanid is a nitroimidazole antibiotic in late-phase clinical testing as a component of several novel antituberculosis (anti-TB) regimens. A population pharmacokinetic model for pretomanid was constructed using a Bayesian analysis of data from two phase 2 studies, PA-824-CL-007 and PA-824-CL-010, conducted with adult (median age, 27 years) patients in Cape Town, South Africa, with newly diagnosed pulmonary TB. Combined, these studies included 63 males and 59 females administered once-daily oral pretomanid doses of 50, 100, 150, 200, 600, 1,000, or 1,200 mg for 14 days. The observed pretomanid plasma concentration-time profiles for all tested doses were described by a one-compartment model with first-order absorption and elimination and a sigmoidal bioavailability dependent on dose, time, and the predose fed state. Allometric scaling with body weight (normalized to 70 kg) was used for volume of distribution and clearance, with the scaling exponents equal to 1 and 3/4, respectively. The posterior population geometric means for the clearance and volume of distribution allometric constants were 4.8 ± 0.2 liters/h and 130 ± 5 liters, respectively, and the posterior population geometric mean for the half-maximum-effect dose for the reduction of bioavailability was 450 ± 50 mg. Interindividual variability, described by the percent coefficient of variation, was 32% ± 3% for clearance, 17% ± 4% for the volume of distribution, and 74% ± 9% for the half-maximum-effect dose. This model provides a dose-exposure relationship for pretomanid in adult TB patients with potential applications to dose selection in individuals and to further clinical testing of novel pretomanid-containing anti-TB regimens.

Modeling and Simulation of Pretomanid Pharmacodynamics in Pulmonary Tuberculosis Patients

“…The EBA values calculated using either TTP or log 10 CFU were ordered as EBA 0Ϫ2 Ͻ EBA 0Ϫ14 Ͻ EBA 2Ϫ14 for all of the once-or twice-daily dosages. The ranking is consistent with the pretomanid plasma exposure (peak concentration, or 24-h area under the concentration-time curve) at the beginning of dose administration being nearly half that achieved as steady state is approached approximately 4 days after the start of treatment (25). The EBA values calculated with either TTP or CFU data are comparable, with the half-maximum effect doses being nearly equal for TTP and CFU calculated values.…”

“…Drug exposure was defined as C ϭ C(t) ϭ f•C p (t)/MIC, where f is the free drug fraction, MIC is the minimum inhibitory concentration, and C p is the concentration of pretomanid in plasma. Pretomanid PK equations for the calculation of C p were described previously (25) and require the specification of a dosage regimen and parameter values for oral bioavailability, absorption, volume of distribution, and clearance, which, together with values for f and MIC, were considered here as given model inputs and covariates. The equation for T was derived from the equation for B through an equality between the time rates of change for log(B) and T, with the liquid culture time constant ( L ) as a conversion factor.…”

“…As the MIC measurements were not available throughout treatment, and as no participant with recorded MICs had both values different from Ͻ0.1 g/ml, a single MIC value equal to 0.1 g/ml was set as a covariate for each individual, with the implication of pretomanid-susceptible TB for all of the included study participants. PK covariates consisted of individual point values for total body weight, oral absorption, distribution, and clearance, which together with a free drug fraction of f ϭ 0.1 were determined previously (25). The values for f and MIC in the PD model equations served as scale factors for the pretomanid plasma exposure.…”

“…The 90% confidence intervals for uncertainty in the predicted percentiles (calculated using a binomial proportion with 10,000-MC-iteration sample sizes) corresponded to errors of less than 1%. The corresponding MC plasma PK simulation plots with the same percentile summaries were shown previously (25). The predicted population distributions for CFU counts and TTP were used to calculate each of the primary and secondary efficacy outcomes for all of the pretomanid treatment arms, which consisted of the EBA measurements from day 0 to day 2 (EBA 0Ϫ2 ), day 2 to day 14 (EBA 2Ϫ14 ), and day 0 to day 14 (EBA 0Ϫ14 ).…”

“…The present study describes a PD model for pretomanid in adult patients with pulmonary TB disease. A structural model for the initial time course of sputum mycobacterial load was developed by combining a standard model for antimicrobial drug effect (24) with previously reported PK equations for pretomanid concentrations in plasma (25) and with a functional relationship between CFU counts and TTP that was based on a previously described correlation between their corresponding EBA values (23). Population-and individual-level parameter estimates were obtained using Bayesian hierarchical modeling (26) with the individual participant data from CL-007 and CL-010.…”