Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations

Reddy, Venkatesh Pilla; Bui, Khanh; Scarfe, Graeme; Zhou, Diansong; Learoyd, Maria

doi:10.1002/cpt.1103

Cited by 55 publications

(42 citation statements)

References 45 publications

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“…In this study, we found a 13% increase and 13% decrease in olaparib C max and a 15% and 8% increase in olaparib AUC seen in patients with mild or moderate hepatic impairment, respectively, vs those with normal hepatic function; these variations in olaparib exposure were not considered clinically relevant 19,20 . Variation in olaparib exposure was notable in the moderate hepatic impairment group; however, this was largely because of 1 patient who had increased exposure to olaparib (indicated by AUC 0–t and C max values; see the Supplementary Materials for further information on this patient).…”

Section: Discussionmentioning

confidence: 66%

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

Rolfo

Isambert

Italiano

et al. 2020

Brit J Clinical Pharma

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Aims Olaparib, a potent oral poly(ADP‐ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or moderate hepatic impairment to provide dosing recommendations. Methods This Phase I open‐label study assessed the PK, safety and tolerability of single doses of olaparib 300‐mg tablets in patients with advanced solid tumours. Patients had normal hepatic function (NHF), or mild (MiHI; Child–Pugh class A) or moderate (MoHI; Child–Pugh class B) hepatic impairment. Blood was collected for PK assessments for 96 hours. Patients could continue taking olaparib 300 mg twice daily for long‐term safety assessment. Results Thirty‐one patients received ≥1 dose of olaparib and 30 were included in the PK assessment. Patients with MiHI had an area under the curve geometric least‐squares mean (GLSmean) ratio of 1.15 (90% confidence interval 0.72, 1.83) and a GLSmean maximum plasma concentration ratio of 1.13 (0.82, 1.56) vs those with NHF. In patients with MoHI, GLSmean ratio for area under the curve was 1.08 (0.66, 1.74) and for maximum plasma concentration was 0.87 (0.63, 1.22) vs those with NHF. For patients with mild or moderate hepatic impairment, no new safety signals were detected. Conclusion Patients with MiHI or MoHI had no clinically significant changes in exposure to olaparib compared with patients with NHF. The safety profile of olaparib did not differ from a clinically relevant extent between cohorts. No olaparib tablet or capsule dose reductions are required for patients with MiHI or MoHI.

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Section: Discussionmentioning

confidence: 66%

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

Rolfo

Isambert

Italiano

et al. 2020

Brit J Clinical Pharma

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“…PBPK modeling has been widely used in drug development to support development decisions, pediatric dose selection, and regulatory submissions and labeling . In the current analysis, a PBPK model of acalabrutinib and its metabolite ACP‐5862 was developed by integrating physiochemical properties, in vitro metabolism data, and clinical PK results and was subsequently verified using available DDI clinical data and then applied to prospective predictions of acalabrutinib‐drug combinations for which no clinical data were available.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Drug–Drug Interaction Potential of Acalabrutinib and Its Active Metabolite, ACP‐5862, Using a Physiologically‐Based Pharmacokinetic Modeling Approach

Zhou

Podoll²,

Yang³

et al. 2019

CPT Pharmacom & Syst Pharma

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Acalabrutinib, a selective, covalent Bruton tyrosine kinase inhibitor, is a CYP 3A substrate and weak CYP 3A/ CYP 2C8 inhibitor. A physiologically‐based pharmacokinetic (PBPK) model was developed for acalabrutinib and its active metabolite ACP ‐5862 to predict potential drug–drug interactions ( DDIs ). The model indicated acalabrutinib would not perpetrate a CYP 2C8 or CYP 3A DDI with the sensitive CYP substrates rosiglitazone or midazolam, respectively. The model reasonably predicted clinically observed acalabrutinib DDI with the CYP 3A perpetrators itraconazole (4.80‐fold vs. 5.21‐fold observed) and rifampicin (0.21‐fold vs. 0.23‐fold observed). An increase of two to threefold acalabrutinib area under the curve was predicted for coadministration with moderate CYP 3A inhibitors. When both the parent drug and active metabolite (total active components) were considered, the magnitude of the CYP 3A DDI was much less significant. PBPK dosing recommendations for DDIs should consider the magnitude of the parent drug excursion, relative to safe parent drug exposures, along with the excursion of total active components to best enable safe and adequate pharmacodynamic coverage.

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“…patients with cancer (and what type of cancer) or without cancer] included in these 14 studies were limited ( Figure 3 ). Of the remaining 10 drugs with a peer-reviewed publication describing dosing and/or pharmacokinetics according to the Child-Pugh criteria, only 3 drugs had studies in patients with cancer [HCC for lenvatinib 14 ; mixed tumor types (including ovarian cancer) for olaparib 15 , 16 ; solid tumors for osimertinib 17 ] ( Table 1 and Figure 3 ). Moreover, these peer-reviewed studies were all limited in enrollment size ( N ≤ 33 patients) ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…2019;105:229-241. 15 Patient number: 23 patients (normal hepatic function, n = 13; Child-Pugh class A, n = 9; Child-Pugh class B results were ongoing at time of abstract publication) Patient characteristics: major tumor types included ovarian (17%), breast (13%), and colon (13%) with chronic hepatic impairment where liver metastases were not the sole reason for any changes in liver function Osimertinib For the treatment of patients with metastatic epidermal growth factor receptor T790M mutation positive non-small-cell lung cancer Grande et al. J Pharmacol Exp Ther .…”

Section: Resultsmentioning

confidence: 99%

A review of the evidence base for utilizing Child-Pugh criteria for guiding dosing of anticancer drugs in patients with cancer and liver impairment

Palmieri

Macpherson

2021

ESMO Open

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As the liver is vital for the metabolism of many anticancer drugs, determining the correct starting doses in cancer patients with liver impairment is key to safe prescription and prevention of unnecessary adverse effects. Clinicians typically use liver function tests when evaluating patients; however, prescribing information and summaries of product characteristics often suggest dosing of anticancer drugs in patients with liver impairment based on the Child-Pugh criteria, even though the criteria were not developed for this purpose. In this review, we assessed all the oncological small molecule and cytotoxic drugs approved by the United States Food and Drug Administration (FDA) over a 5-year period from 2014 to 2018. The various entry criteria related to these drugs—with respect to hepatic function—in key pivotal studies were compared with their approved dosing recommendations found in prescribing information and summaries of product characteristics. We found that 46% of drugs have dosing recommendations based on Child-Pugh criteria alone, despite the fact that only 8% of these drugs were tested within studies that used the Child-Pugh criteria as entry criteria. Moreover, we note that the data used to make recommendations based on Child-Pugh criteria are typically from small studies that may lack an appropriate patient population. We propose that these findings, along with details surrounding the development of the Child-Pugh criteria, call into question the validity and appropriateness of using Child-Pugh criteria for dosing recommendations of anticancer drugs.

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Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations

Cited by 55 publications

References 45 publications

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

Evaluation of the Drug–Drug Interaction Potential of Acalabrutinib and Its Active Metabolite, ACP‐5862, Using a Physiologically‐Based Pharmacokinetic Modeling Approach

A review of the evidence base for utilizing Child-Pugh criteria for guiding dosing of anticancer drugs in patients with cancer and liver impairment

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