Background
Integrase strand transfer inhibitors (INSTIs) are the cornerstone of antiretroviral therapy. Herein we describe the absorption, distribution, metabolism and excretion (ADME) properties of GS-3242, a novel potent and selective INSTI with a potential for long-acting injectable (LAI) administration.
Methods
GS-3242 metabolic stability and protein binding were assessed in nonclinical and human liver microsomes and plasma, respectively. Intravenous (IV) pharmacokinetic (PK) studies were conducted in rats, dogs and monkeys, while injectable PK studies were conducted in monkeys. The human systemic clearance (CL) was estimated from in vitro predicted CL adjusted for the in vitro to in vivo disconnect observed in animals. The human volume of distribution at steady state (Vss) was predicted from nonclinical species. Clinical PK was predicted using the scaled metabolic CL and depot release rates observed in monkeys.
Results
In vitro, GS-3242 showed high metabolic stability and high plasma protein binding (> 99.9%) in all species. Following IV administration, the systemic CL of GS-3242 was low in nonclinical species (< 0.25% of hepatic blood flow). The observed in vivo CL was lower than in vitro predicted CL in all nonclinical species tested. The Vss for GS-3242 in nonclinical species approximated the plasma to extracellular fluid volume. Sustained GS-3242 systemic levels, consistent with dissolution-limited depot release, was observed over > 280 days in monkeys following a single subcutaneous (SC) or intramuscular (IM) injection of an aqueous microsuspension. Based on injection-site dermal observations, these formulations were well tolerated. The mean fraction dose release was 64% and 78% after SC and IM administration, respectively. The release rates (krelease) were in the range 0.0003 to 0.0004 h-1, suitable for Q4M+ injectable dosing. The human CL was predicted to be very low and the Vss approximated the plasma volume. Assuming complete and optimal parenteral release of the drug, GS-3242 is projected to provide Q3M+ coverage above the target plasma exposures.
Conclusions
These nonclinical ADME properties support the development of GS 3242 as a novel INSTI with potential to enable LAI administration for the treatment of HIV