Physiologically Based Pharmacokinetic Model Predictions of Panobinostat (LBH589) as a Victim and Perpetrator of Drug-Drug Interactions

Abstract

Panobinostat (Farydak) is an orally active hydroxamic acid-derived histone deacetylase inhibitor used for the treatment of relapsed or refractory multiple myeloma. Based on recombinant cytochrome P450 (P450) kinetic analyses in vitro, panobinostat oxidative metabolism in human liver microsomes was mediated primarily by CYP3A4 with lower contributions by CYP2D6 and CYP2C19. Panobinostat was also an in vitro reversible and time-dependent inhibitor of CYP3A4/5 and a reversible inhibitor of CYP2D6 and CYP2C19. Based on a previous clinical drug-drug interaction study with ketoconazole (KTZ), the contribution of CYP3A4 in vivo was estimated to be ∼40%. Using clinical pharmacokinetic (PK) data from several trials, including the KTZ drug-drug interaction (DDI) study, a physiologically based pharmacokinetic (PBPK) model was built to predict panobinostat PK after single and multiple doses (within 2-fold of observed values for most trials) and the clinical DDI with KTZ (predicted and observed area under the curve ratios of 1.8). The model was then applied to predict the drug interaction with the strong CYP3A4 inducer rifampin (RIF) and the sensitive CYP3A4 substrate midazolam (MDZ) in lieu of clinical trials. Panobinostat exposure was predicted to decrease in the presence of RIF (65%) and inconsequentially increase MDZ exposure (4%). Additionally, PBPK modeling was used to examine the effects of stomach pH on the absorption of panobinostat in humans and determined that absorption of panobinostat is not expected to be affected by increases in stomach pH. The results from these studies were incorporated into the Food and Drug Administration-approved product label, providing guidance for panobinostat dosing recommendations when it is combined with other drugs.

Food Effect Projections via Physiologically Based Pharmacokinetic Modeling: Predictive Case Studies

“…For ribociclib, absorption rate was not driven by its solubility and dissolution in the gut, but rather by its intestinal permeability and gastric emptying. This assessment was consistent with a previous case example of another weakly basic drug with a dose <100 mg 26 dthat is, demonstrated no AUC and C max changes as predicted over a gastric pH range of <1 to 8.…”

A Drug‐Drug Interaction Study to Evaluate the Effect of TAS‐303 on CYP3A Activity in the Small Intestine and Liver

“…Thus, there is a marked discrepancy between the estimated and actual values for the AUC ratio. We suggest some possible reasons for this discrepancy: uncertainties in key input parameters, such as the K deg of CYP3A, K i , and K inact of TAS‐303, may be alienated from in vivo data; the differential equations for intestinal inhibition implemented in the DDI simulator provide a static rather than dynamic model, and not accounting for the intestinal tissue binding of TAS‐303 in this model (the unbound fraction was assumed to be unity) may lead to an overestimation of unbound TAS‐303 concentration in enterocytes and its inhibitory effect on intestinal CYP3A activity . To reasonably describe the observed DDI between TAS‐303 and simvastatin, the current PBPK model of TAS‐303 needs to be further refined based on emerging preclinical and clinical findings through the future development of TAS‐303.…”

Requirements to Establishing Confidence in Physiologically Based Pharmacokinetic (PBPK) Models and Overcoming Some of the Challenges to Meeting Them

“…BCS Class II-IV drugs with their solubility-and/or permeability-limited, transporter-dependent exposure are subject to absorption and DDI challenges that can be addressed with PBPK. Applications include absorption [20,21], PPI effect [22], food effect prediction [23,24], bioequivalence assessment through IVIVC for getting a biowaiver for formulation bridging, and DDI assessment [25][26][27][28][29][30], to name a few. A comprehensive list of applications is covered by Shebley et al [7].…”