PT-011 - DEVELOPING A SIMULTANEOUS PLASMA AND CENTRAL NERVOUS SYSTEM POPULATION PHARMACOKINETIC MODEL FOR DOLUTEGRAVIR EXPOSURE

B. Ho¹, M. Zhang², S. Letendre^3,4, R. Ellis^5,6, D. Franklin^7,6, A. Bang⁸, G. Morse², D. Mager⁹, N. Smith², Q. Ma²; ¹University at Buffalo, Buffalo, New York, USA, ²Division of Clinical and Translational Therapeutics, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA, ³Department of Medicine, University of California San Diego, San Diego, California, USA, ⁴Department of Psychiatry, University of California San Diego, San Diego, California, USA, ⁵Department of Neuroscience, University of California, San Diego, San Diego, California, USA, ⁶Department of Psychiatry, University of California, San Diego, San Diego, California, USA, ⁷HIV Neurobehavioral Research Center, San Diego, California, USA, ⁸Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA, ⁹Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.

Background: Neuropsychiatric adverse events (NP-AEs) associated with dolutegravir (DTG) administration have emerged as a critical factor necessitating DTG discontinuation in affected patients. Therefore, the study aim was to develop a population pharmacokinetic (PopPK) model to simultaneously capture the distribution characteristics of DTG in both plasma and cerebrospinal fluid (CSF) to evaluate the potential influence of CNS DTG on NP-AE occurrence.

Methods: Plasma and CSF samples were obtained from 45 HIV-infected individuals for analysis. Additional plasma concentration-time profiles of 16 healthy volunteers from a previously published study were included to augment the dataset. Structural models were tested sequentially using NONMEM (Icon, v7.5) to simultaneously characterize the distribution of DTG in the plasma and CSF. The impact of age and total concomitant medications on DTG pharmacokinetics was also evaluated as covariates. Model fit was assessed by objective function value and goodness-of-fit diagnostics, and the model was validated with bootstrap analysis.

Results: A total of 243 DTG plasma (a subset of 165 from digitized literature) and 35 CSF concentrations were included in the PopPK analysis. A one-compartment model with first-order lagged absorption utilizing a biophase compartment to describe CSF DTG concentration, and proportional residual variability adequately described the PK of DTG simultaneously in plasma and CSF. Testing age or concomitant medication use as either a continuous or categorical covariate failed to produce a statistically significant impact. Drug entry to the CNS (Kin) was estimated as being 0.247 h-1 (Bootstrap 95% CI 0.183-0.453), and effectively characterized CSF DTG concentrations.

Conclusion: Our PopPK model provides a foundational framework for assessing DTG exposure simultaneously in plasma and CSF, as well as assessing potential covariates and HIV inhibition target attainment. Overall, further exploring DTG pharmacodynamics in the CNS and associations with NP-AEs will be pivotal in assessing the impact of low DTG CNS concentrations on long-term HIV management.