Bridging Olaparib Capsule and Tablet Formulations Using Population Pharmacokinetic Meta-analysis in Oncology Patients

Zhou, Diansong; Li, Jianguo; Bui, Khanh; Learoyd, Maria; Berges, Aliénor; Milenkova, Tsveta; Al‐Huniti, Nidal; Tomkinson, Helen; Xu, Hongmei

doi:10.1007/s40262-018-0714-x

Cited by 26 publications

(29 citation statements)

References 22 publications

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“…The patient characteristics are summarized in Table S3. All these studies were included in the population PK analysis, and the model was previously published . Briefly, a two‐compartment model with sequential zero‐first‐order absorption and first‐order elimination with different absorption parameters for capsule and tablet formulations reasonably described the olaparib PK profiles.…”

Section: Methodsmentioning

confidence: 99%

“…The final Cox proportional hazards model was applied to predict HR after steady‐state 200 and 300 mg b.i.d. tablet doses, in which the geometric mean C max,ss and/or AUC ss obtained from post hoc estimates were applied …”

Section: Methodsmentioning

confidence: 99%

“…capsule dose and 300 mg b.i.d. tablet dose where the geometric mean C max,ss and/or AUC ss obtained from post hoc estimates were applied …”

Section: Methodsmentioning

confidence: 99%

“…An integrated population pharmacokinetic (PK) analysis, which combined PK data from different patient populations, was developed to evaluate the impact of formulations, prior line of treatment, disease severity, tumor types, or other relevant factors on the PK of olaparib . The steady‐state geometric mean area under the curve (AUC) and peak plasma concentration (C max ) following 300 mg tablet twice daily were 49.0 μg*hour/mL and 7.7 μg/mL, respectively .…”

mentioning

confidence: 99%

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Efficacy and Safety Exposure‐Response Analyses of Olaparib Capsule and Tablet Formulations in Oncology Patients

Zhou

Learoyd

et al. 2019

Clin Pharma and Therapeutics

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Olaparib is a poly ADP-ribose polymerase inhibitor that induces synthetic lethality in tumors with deficient homologous recombination repair. Population exposure-response analyses were performed to evaluate the efficacy and safety of olaparib exposure in patients with cancer. Data from multiple phase I/II/III clinical studies from both capsule and tablet formulations were combined for efficacy (N = 410) and safety (N = 757) analyses. Exposureprogression-free survival (Cox proportional hazards model indicated that a 300 mg b.i.d. tablet was statistically superior to the 200 mg b.i.d. tablet dose (hazard ratio of 0.96), although the difference was small. Exposure-safety logistic regression models and hemoglobin models predicted similar probability of safety events or hemoglobin decrease with largely overlapping 95% confidence intervals at 300 mg b.i.d. tablet, 200 mg b.i.d. tablet, and 400 mg b.i.d. capsule. The analyses provided key assessments to support the approval of olaparib 300 mg tablet therapeutic dose in patients with ovarian and breast cancer, regardless of their breast cancer (BRCA) mutation status.Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that play an important role in various cellular processes. 1 In tumor cells that lack functional components of homologous recombination repair (such as mutations in breast cancer (BRCA1 and BRCA2), DNA double-strand breaks cannot be repaired accurately or effectively and will result in tumor cell death. 2 Olaparib (Lynparza, AstraZeneca, Cambridge, UK) is a first-inclass oral PARP inhibitor. 2 The olaparib capsule formulation was first marketed in 2014 and has received marketing approval for the treatment of patients with BRCA mutated ovarian cancer in more than 50 countries, including those in the European Union, the United States, Switzerland, Australia, and Canada. The recommended capsule dose is 400 mg b.i.d. The olaparib tablet formulation 3 has subsequently received marketing approval for the treatment of patients with relapsed ovarian cancer in the European Union,

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…capsule dose and 300 mg b.i.d. tablet dose where the geometric mean C max,ss and/or AUC ss obtained from post hoc estimates were applied …”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Efficacy and Safety Exposure‐Response Analyses of Olaparib Capsule and Tablet Formulations in Oncology Patients

Zhou

Learoyd

et al. 2019

Clin Pharma and Therapeutics

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“…There are important differences in the pharmacokinetics between the capsule and tablet formulations of olaparib, particularly with respect to bioavailability, absorption and dose exposure (summarized in Table ). Based on Bayesian estimates, the population pharmacokinetic model predicted the geometric mean steady‐state exposure of the 300 mg twice daily tablet was 13% higher compared to that following 400 mg twice daily capsule doses …”

Section: Pharmacokineticsmentioning

confidence: 99%

Practical considerations for clinicians for transitioning patients on maintenance therapy with olaparib capsules to the tablet formulation of olaparib

Friedlander

Shannon

Goh

et al. 2018

Asia-Pac J Clncl Oncology

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Purpose Olaparib was originally formulated as 50 mg capsules with a recommended dose of 400 mg twice daily which requires patients to take 16 capsules a day. More recently, a tablet formulation with equivalent efficacy has become available and reduces the pill burden for patients to two tablets twice daily which is more convenient for patients. However, it is important to understand the key differences between the olaparib capsule and tablet formulations as they are not bioequivalent, and the doses are not interchangeable. Educating patients when transitioning from capsules to tablets is critical to avoid dosing errors and maintain both safety and efficacy of olaparib maintenance therapy. Main recommendations There are no established guidelines on transitioning patients from capsules to tablets. Patients taking 400 mg of the capsules twice daily should be switched to 300 mg of the tablets twice daily. In patients on a reduced dose of 200 mg capsules twice daily, consider switching to 250 mg twice daily of the tablet formulation. In patients on 100 mg capsules twice daily, consider 200 mg tablets twice daily. Particular care should be taken in transitioning patients who are on a reduced dose due to anemia and who have a low hemoglobin (9 g/dL) where a lower dose of the tablets should be considered initially. Close monitoring of patients for the first 3 months with further dose reductions based on tolerability is recommended. The tablet dose can be escalated or de‐escalated depending on tolerance.

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A Phase I dose‐escalation study of two cycles carboplatin‐olaparib followed by olaparib monotherapy in patients with advanced cancer

Geenen

Dackus

Schouten

et al. 2021

Intl Journal of Cancer

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Preclinical studies have shown synergistic effects when combining PARP1/2 inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. After a formulation change of olaparib from capsules to tablets, we initiated a dose finding study of olaparib tablets bidaily (BID) continuously with carboplatin to prepare comparative studies in this patient group. Patients were included in a 3 + 3 dose-escalation schedule: olaparib 25 mg BID and carboplatin area under the curve (AUC) 3 mg*min/mL d1/d22, olaparib 25 mg BID and carboplatin AUC 4 mg*min/mL d1/d22, followed by increasing dose-levels of olaparib from 50 mg BID, 75 mg BID, to 100 mg BID with carboplatin at AUC 4 mg*min/ mL d1/d22. After two cycles, patients continued olaparib 300 mg BID as monotherapy.Primary objective was to assess the maximum tolerable dose (MTD). Twenty-four patients with a confirmed diagnosis of advanced cancer were included. Most common adverse events were nausea (46%), fatigue (33%) and platelet count decrease (33%).

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Bridging Olaparib Capsule and Tablet Formulations Using Population Pharmacokinetic Meta-analysis in Oncology Patients

Cited by 26 publications

References 22 publications

Efficacy and Safety Exposure‐Response Analyses of Olaparib Capsule and Tablet Formulations in Oncology Patients

Efficacy and Safety Exposure‐Response Analyses of Olaparib Capsule and Tablet Formulations in Oncology Patients

Practical considerations for clinicians for transitioning patients on maintenance therapy with olaparib capsules to the tablet formulation of olaparib

A Phase I dose‐escalation study of two cycles carboplatin‐olaparib followed by olaparib monotherapy in patients with advanced cancer

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