PII-078 - POPULATION PHARMACOKINETIC MODELING OF CLOFAZIMINE: CHARACTERIZING THE IMPACT OF CRYPTOSPORIDIOSIS-ASSOCIATED DIARRHEA ON ORAL DRUG PHARMACOKINETICS IN HIV-INFECTED ADULTS.
Thursday, March 23, 2023
5:00 PM – 6:30 PM EDT
C. Zhang1, L. Barrett1, C. Chen2, T. Conrad2, E. Douglas1, M. Gordon3,4, D. Hebert2, D. Hermann5, E. Houpt6, P. Iroh Tam3,7, K. Jere3,4, R. Lindblad2, L. Makhaza3, W. Nedi3, J. Nyirenda3, D. Operario6, J. Phulusa3, G. Quinnan2, L. Sawyer2, H. Thole3, N. Toto7, W. Van Voorhis1, A. Winter2, S. Arnold1; 1University of Washington, Seattle, WA, USA, 2Emmes, Rockville, MD, USA, 3Malawi-Liverpool Wellcome Research Programme, Blantyre, Malawi, 4University of Liverpool, Liverpool, United Kingdom, 5Bill & Melinda Gates Foundation, Seattle, WA, USA, 6University of Virginia, Charlottesville, VA, USA, 7Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
PhD Candidate University of Washington Bellevue, Washington, United States
Background: Cryptosporidium spp. infection can cause serious long-term adverse impact in malnourished children and immunocompromised patients, but no effective treatment is available for these vulnerable populations. Clofazimine showed promise in preclinical models of Cryptosporidium infection but failed to demonstrate efficacy in a Phase 2a clinical trial in HIV-infected adults. The goal of our study was to characterize the population pharmacokinetics (PK) of oral clofazimine and identify significant covariates on clofazimine PK. Methods: We analyzed 428 PK samples from 23 HIV-infected adults with/without Cryptosporidium infection who received clofazimine orally for 5 days in a randomized controlled Phase 2a trial using nonlinear mixed-effects modeling in Phoenix NLME. Various covariates describing cryptosporidiosis-related diarrhea severity or HIV infection status such as number of diarrhea episodes, diarrhea grade, CD4 count, HIV viral load, presence of diarrhea on Day 1, etc. were evaluated in a stepwise fashion. Results: A 2-compartment model with lag time and first-order absorption and elimination best fitted the data. Presence of diarrhea on Day 1 was a significant covariate on bioavailability (p < 0.001) where presence of diarrhea was associated with an approximately 7-fold reduction in bioavailability of clofazimine. Conclusion: The significance of Day 1 diarrhea status on clofazimine bioavailability suggests clofazimine doses may need to be increased to achieve target exposure levels in Cryptosporidium-infected patients with diarrhea. Compromised clofazimine exposure associated with diarrhea might have contributed to the lack of anti-Cryptosporidium efficacy in the clinical trial. Our findings provide new insight for oral drug dose optimization in populations with diarrhea.
