Semi-mechanistic PKPD model of thrombocytopenia characterizing the effect of a new histone deacetylase inhibitor (HDACi) in development, in co-administration with doxorubicin.

Objective: Recent studies [1, 2] demonstrated that the combination of an HDAC inhibitor and DNA-damaging agents has synergistic effects to induce apoptosis. This observation is of potential clinical applicability although several dose-limiting toxicities need to be pre-assessed before dose optimization. The study aim was to develop a PKPD model of thrombocytopenia that considered the PK of an HDACi in development and the PK of the cytotoxic agent doxorubicin and its metabolite doxorubicinol, and to assess the combined drug-induced effects on circulating platelets.

Methods: Eight patients suffering from solid tumors receive 6 x 4-week cycles of oral twice-daily doses of HDACi given 4 h apart and a fixed 15 min IV-infusion dose of doxorubicin, in a 3 out of 4 week regimen in an ongoing phase I dose-escalation study. PK samples for HDACi and doxorubicin (N=230 and 160, respectively), and 202 platelet counts were analyzed with FOCE-I in NONMEM version 7.2. HDACi disposition was described by a three-compartment model with first-order absorption previously developed using internal data. A three-compartment model and a one-compartment model [3] characterized the time course of doxorubin and doxorubicinol, respectively. Sequential modeling was performed, where individual Bayesian estimates of PK parameters were fixed in subsequent PD modeling. A semi-physiological model [4], incorporating stem cell proliferation inhibition drug effect from HDACi previously developed from the same structure as the myelosuppression model described by Friberg et al. [5,6], was further refined and the effect of doxorubicin was added. Patient baseline characteristics were modeled using the B2 method [7].

Results: An Imax and power models (i.e. Slope × Concentration^Hill) describing respectively HDACi and doxorubicin for the drug effect on the proliferative cells were found to best characterize the platelet data. Incorporation of an interaction between the two drugs (INT), implemented in the concentration-effect model as 〖Eff〗_( HDACi)+〖Eff〗_DOXO+ INT×〖Eff〗_HDACi×〖Eff〗_DOXO did not further improve the model. A mean transit time through the chain of non-proliferative cells of 104 h, a feedback parameter of 0.239 and a platelet baseline value of 277×109 /L were estimated. Model evaluation using visual prediction checks (VPC) showed that the resulting PKPD model described adequately well the 80% PI of the data.

Conclusions: A PKPD model was developed that integrated the PK of HDACi and doxorubicin to describe their combined effects on the time-course of platelets in the circulation. Thrombocytopenic effects were adequately predicted assuming an additive effect between the two drugs on the proliferative cells. Future refinements of the model are expected with additional dosing regimen data.

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[3]. Callies S. et al. A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979). Cancer Chemother Pharmacol. 2003; 51(2): 107-18.
[4]. Chalret du Rieu et al. Semi-mechanistic thrombocytopenia model of a new histone deacetylase inhibitor (HDACi) in development, with a drug-induced apoptosis of megakaryocytes. PAGE 21 (2012) Abstr 2503 []
[5]. Friberg et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002;20(24):4713-21.
[6]. Friberg and Karlsson. Mechanistic models for myelosuppression. Invest New Drugs. 2003;21(2):183-94.
[7]. Dansirikul et al. Approaches to handling pharmacodynamic baseline responses. J Pharmacokinet Pharmacodyn. 2008;35(3):269-83.

Camille Vong

  • Uppsala University