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

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Physiologically-Based Pharmacokinetic Model Predictions of Panobinostat (LBH589) As a Victim and Perpetrator of Drug-Drug Interactions DMD Fast Forward. Published on September 14, 2017 as DOI: 10.1124/dmd.117.076851 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 76851 Physiologically-based pharmacokinetic model predictions of panobinostat (LBH589) as a victim and perpetrator of drug-drug interactions Heidi J. Einolf, Wen Lin, Christina S. Won, Lai Wang, Helen Gu, Dung Y. Chun, Handan He, James B. Mangold Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA Downloaded from dmd.aspetjournals.org at ASPET Journals on October 1, 2021 1 DMD Fast Forward. Published on September 14, 2017 as DOI: 10.1124/dmd.117.076851 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 76851 Running Title: PBPK Prediction of Panobinostat Drug-Drug Interactions Corresponding Author: Corresponding Author: Downloaded from Heidi J. Einolf, Ph.D. Novartis, One Health Plaza, East Hanover, NJ 07936; Phone: +1-862-778-3119, Fax: +1-973- 781-5023. Email: [email protected] dmd.aspetjournals.org Number of text pages: 33 at ASPET Journals on October 1, 2021 Number of tables: 10 Number of figures: 9 Number of references: 38 Number of words in Abstract: 249 Number of words in Introduction: 748 Number of words in Discussion: 1500 2 DMD Fast Forward. Published on September 14, 2017 as DOI: 10.1124/dmd.117.076851 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 76851 Abbreviations: ADME, absorption, distribution, metabolism, and excretion ACAT, advanced compartmental absorption and transit AUC, area under the concentration-time curve B/P, blood to plasma ratio CI, confidence interval CL, clearance Downloaded from CLint, intrinsic clearance CLint,u, unbound intrinsic clearance dmd.aspetjournals.org Cmax, maximal concentration CLR, renal clearance CYP, cytochrome P450 at ASPET Journals on October 1, 2021 DEX, dexamethasone DDI, drug-drug interactions EMA, European Medicines Agency FDA, Food and Drug Administration fa, fraction of dose absorbed fugut, unbound fraction in the gut fumic, unbound fraction in microsomes fuplasma, unbound fraction in plasma GI, gastrointestinal HLM, human liver microsomes HPLC, high-performance liquid chromatography ka, absorption rate constant 3 DMD Fast Forward. Published on September 14, 2017 as DOI: 10.1124/dmd.117.076851 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 76851 Ki, inhibition constant Km, Michaelis-Menten constant Km,u unbound Michaelis-Menten constant (corrected by fumic) KTZ, ketoconazole PBPK, physiologically-based pharmacokinetics Peff,man, effective permeability in man PK, pharmacokinetics Downloaded from q.d., once a day dosing Qgut, nominal flow through the gut dmd.aspetjournals.org RAF, relative activity factor RIF, rifampin SD, standard deviation at ASPET Journals on October 1, 2021 Tmax, time to reach maximum concentration Vmax, maximum velocity Vss, volume of distribution at steady-state 4 DMD Fast Forward. Published on September 14, 2017 as DOI: 10.1124/dmd.117.076851 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 76851 Abstract Panobinostat (Farydak®) is an orally active hydroxamic acid derived histone deacetylase inhibitor for the treatment of relapsed/refractory multiple myeloma. Based upon recombinant cytochrome P450 (CYP) kinetic analyses in vitro, panobinostat oxidative metabolism in human liver microsomes was found to be primarily mediated by CYP3A4 with lower contributions by CYP2D6 and CYP2C19. Panobinostat was also shown to be an in vitro reversible and time- dependent inhibitor of CYP3A4/5, and a reversible inhibitor of CYP2D6 and CYP2C19. Based Downloaded from upon 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 dmd.aspetjournals.org several trials including the KTZ 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 AUC at ASPET Journals on October 1, 2021 ratios of 1.8). The model was then applied to predict the drug interaction with the strong CYP3A4 inducer, rifampin (RIF) and 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. The absorption of panobinostat is not expected to be affected by increases in stomach pH. The results from these studies were incorporated into the FDA-approved product label, providing guidance for Farydak® dosing recommendations when combined with other drugs. 5 DMD Fast Forward. Published on September 14, 2017 as DOI: 10.1124/dmd.117.076851 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 76851 Introduction Panobinostat (Farydak®, formerly LBH589) is an orally active hydroxamic acid derived histone deacetylase (HDAC) inhibitor for the treatment of relapsed and refractory multiple myeloma (MM). Panobinostat was approved recently by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a combination therapy with bortezomib and dexamethasone (DEX) in patients with relapsed/refractory MM who have received at least two prior therapies containing an immunomodulatory agent and bortezomib. HDAC enzymes Downloaded from catalyze the deacetylation of lysine residues on histones and prevent transcription of genes encoding proteins involved in cell cycle regulation, differentiation and apoptosis (reviewed in dmd.aspetjournals.org Garnock-Jones 2015). Inhibition of HDAC enzymes by drugs like panobinostat causes an increase in histone acetylation, leading to cellular responses such as cell cycle arrest, apoptosis, and delays in mitosis (reviewed in Cheng et al., 2015). The molecular structure of panobinostat at ASPET Journals on October 1, 2021 is shown in Fig. 1. Panobinostat is considered a biopharmaceutics classification system Class I/II -like drug. It is highly permeable and rapidly absorbed after an oral dose in cancer patients with peak levels occurring within 2h (Farydak® prescribing information, 2016 and FDA Clinical Pharmacology Review, 2015). The systemic clearance (CL) was estimated to be 33 L/hr based on population pharmacokinetic (PK) analysis (Savelieva et al., 2015). There is a high first-pass CL with an absolute bioavailability of ~21% (Farydak® prescribing information, 2016). The absorption of panobinostat is altered when the drug is taken with a high-fat meal; 44% reduction in Cmax and delayed Tmax of 1-1.5h, but the AUC is minimally impacted (Shapiro et al., 2012). Solubility of panobinostat lactate anhydrous is pH-dependent, with the highest solubility in buffer pH 3.0 and low solubility at pH 7.6 (Farydak® prescribing information, 2016 and FDA Clinical 6 DMD Fast Forward. Published on September 14, 2017 as DOI: 10.1124/dmd.117.076851 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 76851 Pharmacology Review, 2015). Currently, there are no clinical studies examining an increase of pH on the PK of panobinostat. In the radiolabeled human absorption, disposition, metabolism, and excretion (ADME) study, 44-77% of the oral [14C]-panobinostat dose was recovered in the feces and 29-51% was excreted in urine (Clive et al., 2012). The main elimination pathway of panobinostat in humans was determined to be metabolism, as the mean unchanged panobinostat recovered in urine was only 1.9% of the dose and presence of panobinostat in the feces was found in only one patient (~3.3% of the dose). The minimal recovery of parent drug in feces Downloaded from suggested near-complete oral absorption of panobinostat. The metabolism of panobinostat was extensive in humans; at least 77 distinct metabolites were identified with ~40 observed dmd.aspetjournals.org circulating in plasma (Clive et al., 2012). The prominent metabolic pathways of panobinostat included reduction and hydrolysis of the hydroxamic acid and one- and two-carbon shortening of this side chain, as well as mono-oxygenation, and glucuronidation. Based upon the identity of at ASPET Journals on October 1, 2021 the metabolites present in the excreta, cytochrome P450 (CYP)-mediated oxidative CL was estimated to range from a maximum of 30-47% of the dose (Clive et al., 2012). This data was consistent with the resultant effect of the CYP3A4 strong inhibitor, ketoconazole (KTZ) on panobinostat exposure in patients (increase AUC of 1.8-fold and Cmax of 1.6-fold), suggesting CYP3A4 contribution to total panobinostat CL is ~40% (Hamberg et al., 2011). The purpose of this manuscript is to present the studies and results identifying the CYP enzyme(s) involved in the oxidative metabolism of panobinostat in human liver and determination of their relative contributions in vitro and scaled contributions in vivo. In addition, the in vitro CYP drug-drug interaction (DDI) properties (inhibition and induction) of panobinostat are presented. Based upon these results, as well as the clinical results of the human radiolabeled
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