770: Pharmacokinetics and tolerability of oral 17-hydroxyprogesterone caproate (HPC) relative to intramuscular (IM) HPC

Abstract

To determine the pharmacokinetic profile and assess tolerability of an oral HPC capsule (LPCN 1107) relative to an IM control in healthy non-pregnant women. This was an open-label, 3-period, active controlled study in ten healthy non-pregnant women 18-30 years of age. In Periods 1 and 2 volunteers were administered in a randomized, cross-over fashion, either one dose of LPCN 1107 400 mg (QD) or two doses of LPCN 1107 400 mg given 12 hours apart (Q12) with a standard meal. In Period 3 all subjects received a single dose of HPC 250 mg IM. There was a washout of one week between treatment Periods. Blood samples were collected over 24 hours following QD dosing, 36 hours following Q12 hour dosing and over 30 days following the IM dosing. HPC concentrations in plasma were analyzed using a validated LC-MS/MS method. Steady state simulations (SS) were modeled from single dose pharmacokinetic parameters using WinNonlin. Following administration of HPC the maximum concentration (Cmax, ng/mL) of HPC was 13.5, 23.1, 7.3 and area under the curve (AUC0-t, ng*h/mL) was 69, 173, 2101 for the QD, Q12 and IM treatments respectively. Given the intrinsic difference in dosing regimen between the oral and IM forms, SS was simulated based on single dose pharmacokinetic parameters for the 400 mg Q12 and 250 mg weekly IM doses. The simulated steady state pharmacokinetic parameters showed that 400 mg Q12 exposure was about 55% of weekly 250 mg IM product. LPCN 1107 was well tolerated with no SAEs. This study is the first to report significant oral absorption of HPC. Based on the steady state simulation, LPCN 1107 could provide serum exposures comparable to weekly IM injection at an appropriate dose and the oral treatments demonstrate good dose response. LPCN 1107 is currently in clinical development and if approved, has the potential to become the first oral HPC therapy for the prevention of recurrent preterm birth.