Jos Lommerse (1), Dominique Stickens (2), , Bimjhana Bishwokarma (2), Christopher Joseph Sinz (3), Mark Zielstorff (4), Stella Vincent (5), Jianwu Bai (2), Yonghua Zhu (2), Chi Sung Chiu (2), Andreas Lindauer (1).
Merck Research Laboratories: (1) Quantitative Pharmacology and Pharmacometrics, Oss, (2) Biology-Discovery, Boston, USA, (3) Medicinal Chemistry, Rahway, USA. (4) Pharmacology, Boston, USA, (5) Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Boston, USA.
Objectives: To develop a PKPD model describing the effect of small molecule prolyl hydroxylase (PHD) inhibitors on erythropoietin (EPO) and hemoglobin (Hb) response. To assess if a model based on short-term (1 day) preclinical studies is appropriate to predict long-term (4 weeks) treatment effects in order to accelerate candidate compound selection.
Methods: Small molecule PHD inhibitors mimic hypoxia mediated Hypoxia-Inducible Factor (HIF) stabilization and thereby activate EPO transcription and translation, leading to reticulocyte proliferation and, as a consequence, increasing hemoglobin levels. PHD inhibitors have the potential as a therapy for chronic anemia [1]. An indirect-response model was used to describe the increase in EPO following one or two doses of two small molecule PHD inhibitors to rats. The delay of the EPO response is captured by a series of transit compartments and an initial lag time after the very first dose. NONMEM v7.1 with FOCE INTER was applied for the estimation of model parameters. The PK-EPO model has been combined with a previously published model relating EPO concentrations to Hb change in rats [2]. The reported parameters of this EPO-Hb model were maintained and the Hb response after 4 weeks of treatment were simulated and compared to actually observed data from a different experiment.
Results: The rat PK-EPO model allowed for the simultaneous estimation of compound-independent (i.e. system-specific) parameters, such as the EPO elimination rate (KOUT) or the maximum stimulatory effect (SMAX). For both PHD inhibitors the initial delay of the EPO response was very similar (<2 hrs). The in vivo potency of EPO stimulation (SC50) was estimated to be 40 and 160 M for compounds A and B, respectively, and a relatively high value of the Hill coefficient (~4) was determined. The maximum stimulation was about 10000 times the baseline EPO synthesis rate. Simulations conducted with the combined PK-EPO/EPO-Hb model after long-term treatment were in reasonable agreement with observations from a separate experiment.
Conclusions: PK and EPO data obtained from short-term experiments provide sufficient information to predict effects of small molecule PDH inhibitors on Hb levels after 4 weeks of treatment. This provides an excellent basis for rapid in vivo compound evaluation to screen clinical candidate compounds.
References:
[1] Rabinowitz, MH. Inhibition of Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Oxygen Sensors: Tricking the Body into Mounting Orchestrated Survival and Repair Responses. J Med Chem. 2013 Dec 12;56(23):9369-402. doi: 10.1021/jm400386j. Epub 2013 Aug 27.
[2] Woo S, Krzyzanski W, Jusko WJ. Pharmacodynamic model for chemotherapy-induced anemia in rats. Cancer Chemother Pharmacol. 2008 Jun;62(1):123-33. Epub 2007 Sep 22.
Reference: PAGE 23 () Abstr 3244 [www.page-meeting.org/?abstract=3244]
Poster: Drug/Disease modeling - Other topics