Population Pharmacokinetics of Doravirine and Exposure-Response Analysis in Individuals with HIV-1

Abstract

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1) infection. A population pharmacokinetic (PK) model was developed for doravirine using pooled data from densely sampled phase 1 trials and from sparsely sampled phase 2b and phase 3 trials evaluating doravirine administered orally as a single entity or as part of a fixed-dose combination of doravirine-lamivudine-tenofovir disoproxil fumarate. A one-compartment model with linear clearance from the central compartment adequately described the clinical PK of doravirine. While weight, age, and healthy versus HIV-1 status were identified as statistically significant covariates affecting doravirine PK, the magnitude of their effects was not clinically meaningful. Other intrinsic factors (gender, body mass index, race, ethnicity, and renal function) did not have statistically significant or clinically meaningful effects on doravirine PK. Individual exposure estimates for individuals in the phase 2b and 3 trials obtained from the final model were used for subsequent exposure-response analyses for virologic response (proportion of individuals achieving <50 copies/ml) and virologic failure. The exposure-response relationships between these efficacy endpoints and doravirine PK were generally flat over the range of exposures achieved for the 100 mg once-daily regimen in the phase 3 trials, with a minimal decrease in efficacy in individuals in the lowest 10th percentile of steady-state doravirine concentration at 24 h values. These findings support 100 mg once daily as the selected dose of doravirine, with no dose adjustment warranted for the studied intrinsic factors.

Keywords: doravirine; exposure-response modeling; pharmacokinetics; population pharmacokinetics.

FIG 1

Effect of intrinsic factors on doravirine steady-state AUC_0–24, C_max, and C₂₄ (the population PK [popPK] geometric mean ratio [GMR] and 90% confidence interval [CI] shown are based on a simulation of 1,000 individuals with HIV-1 per covariate subgroup for categorical covariates or a total of 1,000 individuals with HIV-1 for continuous covariates). AUC, area under the concentration-time curve; C_max, maximum plasma concentration; C₂₄, concentration at 24 h; RI, renal impairment; ref, reference value.

FIG 2

Predicted and observed proportion of individuals achieving HIV-1 RNA levels of <50 copies/ml (A) and with protocol-defined virologic failure (B) as a function of doravirine steady-state C₂₄ quartiles following administration of doravirine at 25 to 200 mg QD with FTC-TDF (n = 217). The heavy solid lines represent the mean predicted exposure-response relationship. The shaded areas represent the 95% CI of the prediction. Markers summarize the observed endpoint frequency (the median and 95% CI are shown) by C₂₄ quartile. Horizontal box plots denote the distribution of individual C₂₄ values at the 25-, 50-, 100-, and 200-mg QD doses in P007, where the point is the median, the box corresponds to the 25th and 75th percentiles, and the whiskers correspond to the 5th and 95th percentiles.

FIG 3

Predicted and observed proportions of individuals with HIV-1 achieving <50 copies/ml as a function of the doravirine steady-state C₂₄ deciles stratified by screening HIV-1 RNA level following administration of doravirine at 100 mg QD with FTC-TDF or ABC-3TC or QD administration of doravirine-3TC-TDF (n = 730). The solid lines represent the mean predicted exposure-response relationship (by stratum). The shaded areas represent the 95% CI of the prediction. Markers summarize the observed endpoint frequency (the median and 95% CI are shown) by C₂₄ quartile.

FIG 4

Predicted and observed proportions of individuals with HIV-1 achieving <50 copies/ml as a function of doravirine steady-state C₂₄ deciles, excluding individuals with at least one sample with a C₂₄ BLQ following administration of doravirine at 100 mg QD with FTC-TDF or ABC-3TC or QD administration of doravirine-3TC-TDF (n = 698), using a log-linear logistic regression model (A) and a linear logistic regression model (B). The solid lines represent the mean predicted exposure-response relationship. The shaded areas represent the 95% CI of the prediction. Markers summarize the observed endpoint frequency (the median and 95% CI are shown) by C₂₄ quartile.

FIG 5

Predicted and observed proportions of individuals with HIV-1 with protocol-defined virologic failure as a function of doravirine steady-state C₂₄ deciles following administration of doravirine at 100 mg QD with FTC-TDF or ABC-3TC or QD administration of doravirine-3TC-TDF (n = 730). The solid line represents the mean predicted exposure-response relationship. The shaded area represents the 95% CI of the prediction. Markers summarize the observed endpoint frequency (the median and 95% CI are shown) by C₂₄ quartile.