Kamunkhwala Gausi1, Paolo Denti1, Lubbe Weisner1, Carole Wallis2, Carolyne Onyango-Makumbi3, Tsungai Chipato4, Gerhard Theron5, Sarah Bradford6, Diane Costello7, Renee Browning8, Nahida Chakhtoura9, Adriana Weinberg10, Grace Montepiedra11, Amita Gupta12 and the IMPAACT P1078 (TB APPRISE) Study Group Team13
1. Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa; 2. BARC Laboratories Africa, Johannesburg, South Africa; 3. Makerere University - Johns Hopkins University Research Collaboration, Kampala, Uganda; 4. University of Zimbabwe College of Health Sciences, Dept of Obstetrics and Gynaecology, Harare, Zimbabwe; 5. Department of Obstetrics and Gynecology, Stellenbosch University, Western Cape, South Africa; 6. FHI 360, Durham, NC, USA; 7. University of California Los Angeles, Los Angeles CA, USA; 8. Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; 9. NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda MD, USA; 10. University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; 11. Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Objectives:
Tuberculosis (TB) predominantly affects women of reproductive age and pregnant women are at elevated risk of progression from latent to active TB (2). TB during pregnancy or early postpartum can result in adverse maternal outcomes, infant TB, or death (3). World Health Organization guidelines recommend >6 months of isoniazid preventive therapy (IPT) for all people living with HIV from low- and middle-income countries (LMIC) where TB is endemic receive, including pregnant women (4). Since no information is available on the pharmacokinetics of isoniazid given as IPT in pregnancy concomitantly with ART, we evaluated these factors in a study.
Methods:
HIV-infected pregnant women at 14 to 34 weeks of gestation either established on or starting ART were recruited from 8 LMIC into a phase IV randomized, double-blind placebo-controlled multicenter international trial (IMPAACT P1078). The study had two arms: Arm A (immediately started on isoniazid 300 mg daily for 28 weeks, then placebo) and Arm B (started on placebo, then switched to isoniazid 300 mg daily at 12 weeks postpartum). A subset of women underwent intensive PK sampling (pre-dose, 1, 2, 4, 6, 8, and 12 hours after isoniazid dosing), while the remaining women underwent sparse PK sampling, with one single sample drawn around 2 hours after a self-reported dose. Sampling occurred once during pregnancy at ≥2 weeks after recruitment and again at 12-21 weeks after delivery. Genetic samples were collected to identify the genotype of NAT2, which was then used to categorize patients into extensive, intermediate or slow acetylators (5). The intensive data was used to develop the base model since the women were monitored closely (the dosing time for intensively sampled patients was monitored while the sparse sampled was safe-reported) and had more sampling time points. Then the sparse data was fitted on the model developed using the intensive data and using this model outliers in the sparse data where identified and removed from modeling. Records of concentration below the limit of quantification were imputed with half of the lower limit of quantification (LLOQ) value (0.105 ug/ml), and the lower limit of the additive error was fixed to 20% of the respective LLOQ.
Results:
847 women were samples of which 32 were intensively sampled, providing 1315 observations of which 88 outlier observations were removed. 748 (88%) were on efavirenz-based ART, 80 (9%) where on nevirapine and 17 (3%) were on lopinavir and 2 (0%) where on atazanavir. 21% of the patient’s had missing genotype for NAT2. The pharmacokinetics of isoniazid was well described using a two-compartment disposition model with first-order absorption through a chain of transit compartments, and first-order elimination implemented with a well-stirred liver model, able to describe both hepatic clearance and first-pass extraction with the parameter of hepatic intrinsic clearance (CLint). This model required the following assumptions: isoniazid protein binding of 5% and a fixed plasma liver flow of 50 L/h for a typical individual weighing 70 kg (6). Allometric scaling based on fat-free mass was applied on clearance and hepatic plasma flow, and total body weight was applied on volume parameters. The effect of NAT2 genotype on oral clearance was significant as expected and was included in the model. Patients with missing genotype were allocated to either of the three phenotypes using a mixture model with three subpopulations (7). The model predicted a typical patient with fat-free mass of 38 kg to have isoniazid oral clearance values of 13.8, 36.6, and 68.7 L/h if slow, intermediate, or extensive acetylator, respectively. After adjusting for body size and NAT2 genotype, pregnancy was found to increase isoniazid clearance by 26% (Delta OFV=49.6).
Conclusions:
The exposure of isoniazid was decreased during pregnancy, due to increased clearance, with respect to a few weeks after delivery. However, the values of isoniazid clearance in all the three NAT2 acetylator groups in the post-pregnancy phase were higher compared to historical nonpregnant ranges. It is then possible that even in this post-delivery phase the clearance of isoniazid may be larger than in non-pregnant state, but this needs further investigation. The clinical implications of the reduction in exposure of isoniazid on the effectiveness of TB treatment, especially preventive treatment, need further investigation.
References:
[1] UNAIDS. UNAIDS DATA 2017 [Internet]. Geneva; 2017 [cited 2018 Jul 18]. Available from: http://www.unaids.org/sites/default/files/media_asset/20170720_Data_book_2017_en.pdf
[2] C E M, V B. Southern African journal of HIV medicine. [Internet]. Vol. 13, Southern African Journal of HIV Medicine. 2012 [cited 2018 Sep 12]. 182 p. Available from: https://sajhivmed.org.za/index.php/hivmed/article/view/113/184
[3] WHO. TREATMENT OF TUBERCULOSIS Guidelines for treatment of drug-susceptible tuberculosis and patient care [Internet]. Geneva; 2017 [cited 2018 Jul 18]. Available from: http://apps.who.int/iris/bitstream/handle/10665/255052/9789241550000-eng.pdf?sequence=1
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[5] Clemmesen JO, Tygstrup N, Ott P. Hepatic plasma flow estimated according to fick’s principle in patients with hepatic encephalopathy: Evaluation of indocyanine green and d-sorbitol as test substances. Hepatology [Internet]. 1998 Mar 1 [cited 2019 Feb 22];27(3):666–73. Available from: http://doi.wiley.com/10.1002/hep.510270305
[6] Keizer RJ, Zandvliet AS, Beijnen JH, Schellens JHM, Huitema ADR. Performance of Methods for Handling Missing Categorical Covariate Data in Population Pharmacokinetic Analyses. AAPS J [Internet]. 2012 Sep [cited 2019 Feb 28];14(3):601–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22648902
Reference: PAGE 28 (2019) Abstr 8989 [www.page-meeting.org/?abstract=8989]
Poster: Drug/Disease Modelling - Infection