Model‐Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co‐Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy

Abstract

Tuberculosis is the most common cause of death in HIV‐infected patients. Isoniazid is used as a first‐line drug to treat tuberculosis infection. However, variability in isoniazid pharmacokinetics can result in hepatotoxicity or treatment failure. Determination of clinical factors affecting isoniazid pharmacokinetics and metabolic pathways in HIV co‐infected patients is therefore critical. Plasma levels of isoniazid, acetyl‐isoniazid, and isonicotinic acid from 63 patients co‐infected with tuberculosis and HIV were analyzed by liquid chromatography with tandem mass spectrometry followed by nonlinear mixed‐effects modeling. Patients were genotyped to determine acetylator status. Patients were either on concomitant efavirenz‐based antiretroviral therapy or HIV treatment naïve. Clearances of isoniazid were 1.3‐fold and 2.3‐fold higher in intermediate and rapid acetylators, respectively, compared with slow acetylators. Patients on concomitant efavirenz‐based antiretroviral therapy had 64% and 80% higher population predicted clearances of acetyl‐isoniazid and isonicotinic acid, respectively, compared with patients who were HIV treatment naïve. Both sex and CD4 cell count affected the bioavailability of isoniazid. Variability in isoniazid exposure could be reduced by dose adaptions based on acetylator type and sex in addition to the currently used weight bands. A novel dosing strategy that has the potential to reduce isoniazid‐related toxicity and treatment failure is presented.

A Model-Informed Method for the Purpose of Precision Dosing of Isoniazid in Pulmonary Tuberculosis

“…We did not differentiate between acetylator proportions for different ethnicities, which are known to vary [ 47 ]. The other model parameters are also mostly similar to those described previously [ 5 , 17 ]. The estimates for the peripheral volume and intercompartmental clearance for INH vary between the different models.…”

“…The structure of the final PK model is comparable to those previously described [ 5 , 17 , 21 ]. The estimated clearances and proportion of fast NAT2 acetylators described in this model are very similar to those previously described [ 17 ].…”

“…In this project, we have developed a model describing the pharmacokinetics of INH based on a large and diverse dataset. The model should have a wider applicability and be better suited for TDM in various populations compared to previously published models, which were all based on studies from a single country [ 4 , 5 , 17 – 22 ]. We also introduced and evaluated a model-based TDM approach for personalized dosing of INH using sampling at 2 and 4 h or 2, 4, and 6 h after dosing.…”

“…Using a model-based method for TDM has several advantages: it can use flexible sampling times, it allows exposure predictions following dose adjustments, and it can use data from previous sampling occasions for the same patient in the prediction. Available models for INH are often based on data from a single-center study with a limited sample size limiting the generalizability of their use for dose individualization [ 4 , 5 , 17 – 22 ]. The aim of this study was to develop and evaluate a model-based TDM approach for INH in adult patients with pulmonary TB using a population-PK model suitable for dose individualization in programmatic treatment.…”

Influence of N-acetyltransferase 2 (NAT2) genotype/single nucleotide polymorphisms on clearance of isoniazid in tuberculosis patients: a systematic review of population pharmacokinetic models

“…Of the identified 12 studies, nine were carried out in adult TB population [25][26][27][28][29][30][31][32][33], two in pediatric TB [34,35] and one in pregnant TB population [36]. Five studies were conducted in Asian countries, of which two were from China [26,28], one each from Indonesia [25], Korea [27], and Vietnam [34].…”