Yook-Hwan Noh(1), Hyeong-Seok Lim(2), Jee-Woong Son(3), Kyun-Seop Bae(2)
(1) Inje University, Busan Paik Hospital, Korea, (2) Ulsan University, Asan Medical Center, Korea, (3) Hanmi Pharm., Co. Ltd., Korea
Objectives: To develop a population pharmacokinetic (PK) model for HM781-36 and its two metabolites in patients with advanced solid tumors and determine the influence of patient demographics and baseline parameters.
Methods: Blood samples and demographic data were collected from two phase I studies in which adult patients received oral HM781-36B for various malignancies. Fifty-two patients received oral HM781-36B tablets (0.5–32 mg) once daily for 2 weeks [intermittent dosing schedule, 1 cycle for 3 weeks] and another 20 patients received oral HM781-36B tablets (12, 16, 18, 24 mg) once daily for 4 weeks [continuous dosing schedule, 1 cycle for 4 weeks]. Plasma concentration-time data of HM781-36 and HM781-36-M1/-M2 (metabolites) were analyzed with a population approach using NONMEM®.
Results: A total of 72 cases were available for analysis with no exclusions of any enrolled patients. HM781-36 PK was ascribed to a two-compartment model and HM781-36-M1/-M2 PK to one-compartment models. First, the base structural model for the HM781-36 concentration alone was constructed, and then a combined parent-metabolite PK model was made, which estimated both parent and metabolite parameters simultaneously. HM781-36 oral absorption was characterized by first-order input (absorption rate constant [KA] = 1.45 ± 0.23 h-1, inter-individual variability [IIV] = 78.4%). The central volume of distribution of HM781-36 (Vc/F = 185 ± 12.7 L, IIV = 29.2%) was influenced significantly by body weight ( ). The absorption rate constant was influenced by food intake in eight patients who received HM781-36B in the fed state, and the effect was included in the final model. The typical HM781-36 apparent clearance (CL/F) was 34.5 L/h (29.4%CV), with an apparent peripheral volume of distribution (Vp/F) of 164 L (53.5%CV). The typical CLm1/fm1 and CLm2/fm2 of HM781-36-M1/-M2 metabolites were 81.7 L/h (46.9%CV) and 14.4 L/h (57.4%CV), respectively. The final PK model was validated using nonparametric bootstrapping and a visual predictive check.
Conclusions: The population PK data described here suggest that HM781-36 PKs are consistent across most solid tumor types and that the absorption process of HM781-36 is affected by the fed state before dosing. In addition, the first-pass effect was considered a significant factor influencing total bioavailability. HM781-36 PKs are not complicated by patient demographics or baseline factors, other than body weight.
References:
[1] Ritter, C.A. and C.L. Arteaga, The epidermal growth factor receptor-tyrosine kinase: a promising therapeutic target in solid tumors. Semin Oncol, 2003. 30(1 Suppl 1): p. 3-11.
[2] Beal, S.L., L.B. Sheiner, and A.J. Boeckmann, NONMEM Users Guide: Part I-VII (1989-2006). p. Ellicott City, Maryland, USA: Icon Development Solutions.
Reference: PAGE 23 (2014) Abstr 3076 [www.page-meeting.org/?abstract=3076]
Poster: Drug/Disease modeling - Oncology