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Population Pharmacokinetic Analysis of Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis.

ABSTRACT: A population pharmacokinetic (PopPK) model of delamanid in patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) was developed using data from four delamanid clinical trials. The final PopPK data set contained 20,483 plasma samples from 744 patients with MDR-TB receiving an optimized background regimen (OBR). Delamanid PK was adequately described for all observed dosing regimens and subpopulations by a two-compartment model with first-order elimination and absorption, an absorption lag time, and decreased relative bioavailability with increasing dose. Relative bioavailabilities of 200-mg and higher doses (250 and 300 mg) were 76% and 58% of a 100-mg dose, respectively. Relative bioavailability was 26% higher after evening doses than morning doses and 9% higher in outpatient settings than inpatient settings. The rate of absorption was higher, and lag time was shorter, following a morning dose than an evening dose. Relative bioavailabilities in patients in Northeast Asian and Southeast Asian regions were 53% and 40% higher, respectively, than in patients in non-Asian regions. Apparent clearance was higher (to the power of -0.892) in patients with hypoalbuminemia (albumin levels of <3.4 g/dl). Coadministration of efavirenz in patients with HIV increased delamanid clearance by 35%. Delamanid exposure was not affected by age (18 to 64 years), mild or moderate renal impairment, anti-TB antibiotic resistance status, HIV status, or markers of hepatic dysfunction or by concomitant administration of OBR, lamivudine, tenofovir, pyridoxine, CYP3A4 inhibitors and inducers, or antacids. Model evaluation suggested reasonable model fit and predictive power, indicating that the model should prove reliable to derive PK metrics for subsequent PK/PD analyses.

SUBMITTER: Wang X

PROVIDER: S-EPMC7927850 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The blood concentration of isoniazid (INH) is evidently affected by polymorphisms in N-acetyltransferase 2 (NAT2), an enzyme that is primarily responsible for the trimodal (i.e., fast, intermediate, and slow) INH elimination. The pharmacokinetic (PK) variability, driven largely by NAT2 activity, creates a challenge for the deployment of a uniform INH dosage in tuberculosis (TB) patients. Although acetylator-specific INH dosing has long been suggested, well-recognized dosages according to acetylator status remain elusive. In this study, 175 blood samples were collected from 89 pulmonary TB patients within 0.5 to 6 h after morning INH administration. According to their NAT2 genotypes, 32 (36.0%), 38 (42.7%), and 19 (21.3%) were fast, intermediate, and slow acetylators, respectively. The plasma INH concentration was detected by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic (PPK) analysis was conducted using NONMEM and R software. A two-compartment model with first-order absorption and elimination well described the PK parameters of isoniazid. Body weight and acetylator status significantly affected the INH clearance rate. The dosage simulation targeting three indicators, including the well-recognized efficacy-safety indicator maximum concentration in serum (C max; 3 to 6??g/ml), the reported area under the concentration-time curve from 0 h to infinity (AUC0-?; ?10.52??g·h/ml), and the 2-h INH serum concentrations (?2.19??g/ml), was associated with the strongest early bactericidal activity. The optimal dosages targeting the different indicators varied from 700 to 900?mg/day, 500 to 600?mg/day, and 300?mg/day for the rapid, intermediate, and slow acetylators, respectively. Furthermore, a PPK model for isoniazid among Chinese tuberculosis patients was established for the first time and suggested doses of approximately 800?mg/day, 500?mg/day, and 300?mg/day for fast, intermediate, and slow acetylators, respectively, after a trade-off between efficacy and the occurrence of side effects.

Dataset Information

Population Pharmacokinetic Analysis of Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis.

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