POPULATION PHARMACOKINETIC ANALYSIS DEMONSTRATES NO DRUG-DRUG INTERACTIONS BETWEEN CROFELEMER, A NOVEL TREATMENT FOR NONINFECTIOUS DIARRHEA IN HIV+ INDIVIDUALS, AND ANTIRETROVIRAL THERAPY

Crofelemer, a minimally absorbed, botanically derived, first-in-class antidiarrheal agent, was approved by the US Food and Drug Administration in December 2012 at a dose of 125 mg twice daily for symptomatic relief of noninfectious diarrhea in adult patients with HIV/AIDS on ART. Secretory diarrhea, particularly noninfectious diarrhea, is associated with combination antiretroviral therapy (ART) therapy. It is characterized by increased secretion of chloride ions and the movement of sodium and water into the intestinal lumen as a result of cyclic adenosine monophosphate (cAMP)–stimulated cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channel (CaCC) activation by HIV, ART, or bacterial enterotoxins. Crofelemer is a dual inhibitor of CFTR and CaCC in the intestinal epithelium. For patients with HIV/AIDS receiving combination ART, comorbidities requiring management or treatment with other therapies increase the potential for drug-drug interactions (DDI) with ART6; clinically significant DDI have been reported in 27% to 40% of patients with HIV/AIDS taking ART. Significant DDI with ART may be caused by induction or inhibition of major metabolic pathways, or by drug transporters, resulting in reductions in ART efficacy, safety, and tolerability. Purpose (a): To determine the potential for crofelemer to alter the pharmacokinetics (PK) of concomitantly administered ART agents in HIV+ patients in the ADVENT trial. Methods (b): HIV+ adults taking a stable ART regimen for ≥4 weeks, with a history of diarrhea (ie, persistently loose stools despite regular antidiarrheal medication use or ≥1 watery bowel movement per day without regular antidiarrheal use for ≥1 month) and CD4+ count ≥100 cells/μL. ADVENT is a randomized, double-blind, two-stage phase 3 trial (Figure 1) conducted from October 2007 to January 2011 Pharmacokinetic Assessments. A multiple-trough sampling design14 was used to assess population PK. Sample collection for PK assessments occurred at baseline, prior to dosing at randomization, at the end of the placebo-controlled phase (ie, week 4), and at the end of the study (ie, week 24). Immune status was evaluated by analysis of CD4+ cell count and HIV viral load. Crofelemer concentrations were assayed by validated high-performance liquid chromatography with fluorescence detection (Celerion, Lincoln, NE, USA); ART concentrations were assayed by Tandem Labs (Salt Lake City, UT, USA) and the University of North Carolina Clinical Pharmacology and Analytical Chemistry Core Facility (Chapel Hill, NC, USA). Results (c): More than 97.5% of patients in the PK population (n = 353) had received ≥ 3 combination ART regimens before the study. Patients received 126 different combinations of ART; the most frequently used combination ART was EFV, FTC, and TNF (n = 60). All 6 of the most common ARTs demonstrated marked exposure variability during the study (Figure 2). Week 4 and 24 ART steady-state trough drug concentrations in patients receiving crofelemer, regardless of crofelemer dose, were comparable with concentrations obtained during the crofelemer-free period (for example, TNF in Figure 3). Comparable results were demonstrated with RTV, FTC, 3TC, LPV, and EFV (Table 2). Crofelemer had no statistically significant effect on the PK of the 6 most commonly used ARTs in ADVENT, as assessed by the Bonferroni correction approach (Table 2). Administration of crofelemer had no negative impact on clinical immune parameters (HIV viral load and CD4+ cell counts) • In >96% of patients, crofelemer concentrations were below the limit of quantitation (50 ng/mL). Conclusions (d): Crofelemer had no significant effect on the PK of the most frequently-used ART evaluated in this study. Consistent with the absence of effects on ART PK, crofelemer did not adversely affect ART efficacy, based on HIV viral load or CD4+ cell counts. Crofelemer was not systemically absorbed to a significant extent.