Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor

Hamberg, Paul; Woo, Margaret M.; Chen, Lin-Chi; Verweij, Jaap; Porro, Maria Grazia; Zhao, Lily; Li, Wenkui; Biessen, D. van der; Sharma, Sunil; Hengelage, Thomas; Jonge, Maja de

doi:10.1007/s00280-011-1693-x

Cited by 42 publications

(41 citation statements)

References 16 publications

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“…After 4 weeks of persisting grade 4 leukopenia, POS treatment was stopped as presumed culprit and leukopenia improved. This interaction could have been predicted based on the interaction of panobinostat with ketoconazole where panobinostat maximum serum concentrations were increased by an average of 1.6‐fold …”

Section: Discussionmentioning

confidence: 99%

High‐dose posaconazole for azole‐resistant aspergillosis and other difficult‐to‐treat mould infections

Schauwvlieghe

Buil

Verweij

et al. 2019

Mycoses

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Summary Background Oral follow‐up therapy is problematic in moulds with reduced azole‐susceptibility, such as azole‐resistant Aspergillus fumigatus infection. Currently, only intravenous liposomal amphotericin B (L‐AmB) is advocated by guidelines for the treatment of azole‐resistant aspergillosis infections. Preclinical research indicates that high‐dose posaconazole (HD‐POS) might be a feasible option provided that high drug exposure (ie POS serum through levels >3 mg/L) can be achieved and is safe. Objectives To describe our experience with the use of oral HD‐POS as treatment strategies for patients infected with pathogens with a POS MIC close to the clinical breakpoint. Patients/Methods We review evidence supporting the use of HD‐POS and describe our experience on safety and efficacy in 16 patients. In addition, we describe the adverse events (AE) observed in 25 patients with POS concentrations at the higher end of the population distribution during treatment with the licensed dose. Results Sixteen patients were treated intentionally with HD‐POS for voriconazole‐resistant invasive aspergillosis (7/16), mucormycosis (4/16), salvage therapy for IA (4/16) and IA at a sanctuary site (spondylodiscitis) in 1. Grade 3‐4 AEs were observed in 6, and all of them were considered at least possibly related. Grade 3‐4 AEs were observed in 5 of the 25 patients with spontaneous high POS serum through levels considered at least possibly related using Naranjo scale. Conclusions High‐dose posaconazole is a treatment option if strict monitoring for both exposure and for AE is possible.

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Section: Discussionmentioning

confidence: 99%

High‐dose posaconazole for azole‐resistant aspergillosis and other difficult‐to‐treat mould infections

Schauwvlieghe

Buil

Verweij

et al. 2019

Mycoses

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“…However, as CYP3A4 is also a major liver enzyme catalyzing drug metabolism, there is a major concern that ritonavir may increase the serum concentration of panobinostat excessively and cause severe adverse events. However, a clinical study using panobinostat with ketoconazole as a CYP3A4 inhibitor, demonstrated that the combination increased the maximum concentration (Cmax) of panobinostat 1.6-fold and the area under the curve 1.8-fold, without significantly altering the time required to reach Cmax or the half-life (6). The authors of that study concluded that co-administration of panobinostat with CYP3A inhibitors is feasible, as the increases in the parameters of panobinostat pharmacokinetics were not clinically relevant.…”

Section: Discussionmentioning

confidence: 99%

Ritonavir acts synergistically with panobinostat to enhance histone acetylation and inhibit renal cancer growth

Sato

Isono

Ito

et al. 2014

Molecular and Clinical Oncology

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Abstract. There is currently no curative treatment for advanced renal cancer. Enhancing histone acetylation is a promising epigenetic-based therapy for cancer; however, in solid tumors, the efficacy of histone deacetylase (HDAC) inhibitors alone is limited. The human immunodeficiency virus protease inhibitor ritonavir is also a CYP3A4 inhibitor and we hypothesized that combining ritonavir with the HDAC inhibitor panobinostat, one of the substrates of CYP3A4, may effectively eliminate renal cancer cells by enhancing the activity of panobinostat. The combination of ritonavir and panobinostat synergistically inhibited cancer cell growth and cancer cell colony formation, while only slightly inhibiting the growth of renal proximal tubule epithelial cells. This combination significantly induced apoptosis in cancer cells and this apoptosis was considered to be caspase-dependent, since the pan-caspase inhibitor Z-VAD-FMK reduced the number of Annexin V-positive cells. In murine subcutaneous xenograft models using Caki-1 cells, a 10-day treatment with the combination of ritonavir and panobinostat significantly inhibited tumor growth. Panobinostat alone increased histone acetylation in a dose-dependent manner and the co-administration of ritonavir synergistically enhanced this acetylation. Furthermore, this combination inhibited the expression of HDACs, which may also play a role in the enhancement of histone acetylation. Thus, the present study may provide a basis for testing the combination of ritonavir and panobinostat for patients with advanced renal cancer.

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“…Methods for quantitation and pharmacokinetic analysis of erlotinib (24, 25) and panobinostat (26) have been previously published. The disposition of erlotinib in the presence of panobinostat (days 9 and 15) was compared to that shown in the absence of panobinostat (day 8).…”

Section: Methodsmentioning

confidence: 99%

A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Panobinostat, an HDAC Inhibitor, Combined with Erlotinib in Patients with Advanced Aerodigestive Tract Tumors

Gray

Haura

Chiappori

et al. 2014

Clinical Cancer Research

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Purpose Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances anti-proliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in advanced NSCLC and head-and-neck (H&N) cancer patients. Experimental Design Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at 4 planned dose levels (DLs). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre- and post-therapy tumor biopsies for CHK1 expression were assessed. Results Of 42 enrolled patients enrolled, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1–3), and rash and anorexia (grades 1–2). Disease control rates were 54% for NSCLC (n=26) and 43% for H&N (n=7). Of 7 NSCLC patients with epidermal growth factor receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR-wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P=0.43) and overall survival was 41 (estimated) versus 5.2 months (P=0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat’s pharmacodynamic effect in blood, FPB and tumor samples. Low CHK1 expression levels correlated with PFS (P=0.006) and response (P=0.02). Conclusions We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore benefits of HDAC inhibitors in EGFR-mutant NSCLC patients, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1’s predictive role.

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Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor

Cited by 42 publications

References 16 publications

High‐dose posaconazole for azole‐resistant aspergillosis and other difficult‐to‐treat mould infections

High‐dose posaconazole for azole‐resistant aspergillosis and other difficult‐to‐treat mould infections

Ritonavir acts synergistically with panobinostat to enhance histone acetylation and inhibit renal cancer growth

A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Panobinostat, an HDAC Inhibitor, Combined with Erlotinib in Patients with Advanced Aerodigestive Tract Tumors

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