Pharmacokinetics of Dacarbazine and Unesbulin and CYP1A2-Mediated Drug Interactions in Patients With Leiomyosarcoma

Abstract

Unesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5-aminoimidazole-4-carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m² ) was administered to patients with LMS via 1-hour intravenous (IV) infusion on Day 1 of every 21-day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (BIW), starting on Day 2 of every cycle, except for Cycle 2 (C2), where unesbulin was dosed either on Day 1 together with DTIC or on Day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in Cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached C_max immediately or shortly after end of infusion at 1.0 and 1.4 hours (T_max ), respectively. Coadministration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2-mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC C_max by 69.4% and AUC_inf by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m² IV DTIC q21d and 300 mg unesbulin BIW in a staggered regimen is well tolerated in patients with LMS.

FIGURE 1

Pathway of DTIC metabolism. Adopted from Reid et al.⁷, and Ortiz de Montellano. AIC, 5‐aminoimidazole‐4‐carboxamide; DTIC, dacarbazine; MTIC, 5‐[3‐methyl‐triazen‐1‐yl]‐imidazole‐4‐carboxamide; HMMTIC, 5‐[3‐hydroxymethyl‐3‐methyl‐triazen‐l‐yl]‐imidazole‐4‐carboxamide; HPLC, high‐pressure liquid chromatography; P450, cytochrome P450.

FIGURE 2

Study design. DTIC was administered on day 1 of every 21‐day cycle. During cycle 1, the first dose of unesbulin was administered on day 2, then b.i.w. for the remainder of the 21‐day cycle. In cycle 2, subjects received the first dose of unesbulin either (a) simultaneously with DTIC on day 1 (co‐administered) until five PK‐evaluable subjects were dosed or (b) 24 h after DTIC infusion on day 2 (staggered dosing) thereafter. BIW, twice weekly; DTIC, dacarbazine; IV, intravenous; PK, pharmacokinetic; PO, by mouth.

FIGURE 3

Mean DTIC (a) and metabolite AIC (b) plasma concentrations following DTIC 1‐h i.v. infusion on cycle 1 day 1 (dacarbazine alone) and cycle 2 day 1 (co‐administered with unesbulin or 2 to 3 days after last unesbulin administration). AIC, 5‐aminoimidazole‐4‐carboxamide; DTIC, dacarbazine.

FIGURE 4

Mean unesbulin plasma concentration following oral administration (combined data from cycle 1 day 8 and cycle 2 day 1 or cycle 2 day 2).