The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib

Vishwanathan, Karthick; Dickinson, Paul; So, Karen; Thomas, Karen; Chen, Yuh Min; Castro, Javier de; Dingemans, Anne Marie C.; Kim, Hye Ryun; Kim, Joo Hang; Krebs, Matthew; Yang, James Chih‐Hsin; Bui, Khanh; Weilert, Doris; Harvey, R. Donald

doi:10.1111/bcp.13534

Cited by 56 publications

(56 citation statements)

References 49 publications

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“…Patients with cystic fibrosis have highly variable pharmacokinetics and steady‐state sputum concentrations of itraconazole often fall below the minimum inhibitory concentration (MIC 90 ) for A. fumigatus in most subjects . High plasma concentrations of itraconazole can lead to significant drug–drug interactions (DDI) and significantly impact the pharmacokinetics of other drugs through inhibition of cytochrome p450 3A4 in the liver and increasing plasma exposure has been linked to a greater probability for adverse events (AEs) . Poor pharmacokinetics and risks associated with its side effect profile limit itraconazole therapeutic efficacy …”

Section: Introductionmentioning

confidence: 99%

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics

Hava

Tan²,

Johnson³

et al. 2020

Brit J Clinical Pharma

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Aims Oral itraconazole has variable pharmacokinetics and risks of adverse events associated with high plasma exposure. An inhalation formulation of itraconazole (PUR1900) is being developed to treat allergic bronchopulmonary aspergillosis, an allergic inflammatory disease occurring in asthmatics and patients with cystic fibrosis. Methods A 3‐part, open‐label Phase 1 study was conducted to evaluate safety, tolerability and pharmacokinetics of PUR1900. Healthy volunteers (n = 5–6/cohort) received either single (Part 1) or multiple (Part 2) ascending doses of PUR1900 for up to 14 days. In Part 3 stable, adult asthmatics received a single dose of 20 mg PUR1900 or 200 mg of oral Sporanox (itraconazole oral solution) in a 2‐period randomized cross‐over design. Itraconazole plasma and sputum concentrations were evaluated. Results None of the adverse events considered as at least possibly related to study treatment were moderate or severe, and none were classed as serious. The most common was the infrequent occurrence of mild cough. Itraconazole plasma exposure increased with increasing doses of PUR1900. After 14 days, PUR1900 resulted in plasma exposure (area under the concentration–time curve up to 24 h) 106‐ to 400‐fold lower across doses tested (10–35 mg) than steady‐state exposure reported for oral Sporanox 200 mg. In asthmatics, PUR1900 geometric mean maximum sputum concentrations were 70‐fold higher and geometric mean plasma concentrations were 66‐fold lower than with oral Sporanox. Conclusion PUR1900 was safe and well‐tolerated under the study conditions. Compared to oral dosing, PUR1900 achieved higher lung and lower plasma exposure. The pharmacokinetic profile of PUR1900 suggests the potential to improve upon the efficacy and safety profile observed with oral itraconazole.

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Section: Introductionmentioning

confidence: 99%

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics

Hava

Tan²,

Johnson³

et al. 2020

Brit J Clinical Pharma

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“…7 Coadministration of osimertinib with itraconazole (strong CYP3A4 inhibitor) resulted in a minor increase (24% area under the plasma concentration-time curve [AUC] increase) in osimertinib exposure, which was not clinically relevant, and coadministration with rifampicin (CYP3A4 inducer) decreased the maximum plasma concentration after multiple dosing (C ss,max ) and AUC from time zero to the end of dosing interval (AUC τ ) of osimertinib by 73% and 78%, respectively. 12 Recently, it was reported that osimertinib may also cause induction of CYP1A1 enzymes in vitro, 13 although no evidence has been observed in the clinic. 14 P-glycoprotein (P-gp), a 170-kDa glycosylated transmembrane protein, is the most studied drug efflux pump that extrudes a variety of drugs from the cell.…”

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confidence: 99%

Modulation of Fexofenadine Pharmacokinetics by Osimertinib in Patients With Advanced EGFR‐Mutated Non–Small Cell Lung Cancer

Calvo

Lee

Kim

et al. 2019

The Journal of Clinical Pharma

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Osimertinib is a potent, third-generation, irreversible, central nervous system active epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. It is approved for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for patients with T790M-positive advanced NSCLC whose disease has progressed on or after EGFR-TKI therapy. This study investigated the pharmacokinetics (PK) of fexofenadine (P-glycoprotein substrate) following single-and multiple-dose osimertinib in patients with advanced NSCLC who have progressed on prior EGFR-TKI therapy. This open-label, phase 1 study (NCT02908750) comprised the PK phase and continued access phase. The former comprised 2 distinct periods with a 3-to 7-day washout: treatment period 1 (n = 24, fexofenadine 120 mg, day 1) and treatment period 2 (fexofenadine 120 mg + osimertinib 80 mg single dose on days 1 and 39 and osimertinib 80 mg once daily from days 4 to 41). Patients could continue osimertinib 80 mg once daily based on investigator's discretion in the continued access phase. Fexofenadine area under the plasma concentration-time curve and maximum concentration increased by 56% (90% confidence interval [CI], 35.4-78.6) and 76% (90%CI, 49.3-108.3) following coadministration with osimertinib single dose, and by 27% (90%CI, 11.2-45.8) and 25% (90%CI, 5.6-48.1) when given with osimertinib at steady state, respectively. Following osimertinib coadministration, median fexofenadine time to maximum concentration increased by approximately 30 minutes compared with time to maximum concentration following fexofenadine alone. No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P-glycoprotein inhibitor.

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“…23 However, the absolute bioavailability of osimertinib has not been reported. 25,26 However, the strong CYP3A inducer rifampicin significantly decreased the exposure of osimertinib. 24 In PK studies, the concentration and exposure of osimertinib was not affected by coadministration with food, omeprazole, or the CYP3A and P-glycoprotein inhibitor itraconazole.…”

mentioning

confidence: 99%

“…24 In PK studies, the concentration and exposure of osimertinib was not affected by coadministration with food, omeprazole, or the CYP3A and P-glycoprotein inhibitor itraconazole. 25,26 However, the strong CYP3A inducer rifampicin significantly decreased the exposure of osimertinib. 25 For this reason, labeling recommendations for osimertinib include avoidance of strong inducers of CYP3A.…”

mentioning

confidence: 99%

“…25,26 However, the strong CYP3A inducer rifampicin significantly decreased the exposure of osimertinib. 25 For this reason, labeling recommendations for osimertinib include avoidance of strong inducers of CYP3A. 27 Traditionally, a crossover study design has been used to determine absolute bioavailability, whereby an oral dose and an intravenous (IV) dose are administered on separate occasions, with a washout period in between.…”

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confidence: 99%

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Absolute Bioavailability of Osimertinib in Healthy Adults

Vishwanathan

Thomas

et al. 2018

Clinical Pharm in Drug Dev

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Osimertinib is a third-generation, central nervous system-active, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) selective for EGFR-TKI sensitizing and T790M resistance mutations. This phase 1, open-label study (NCT02491944) investigated absolute bioavailability and pharmacokinetics (PK) of oral and intravenous (IV) osimertinib. Ten healthy subjects (21-61 years) received a single oral 80-mg dose concomitantly with a 100 μg (containing 1 μCi) IV microtracer dose of [ C]osimertinib. Oral and IV PK were determined simultaneously for osimertinib and its active metabolites, AZ5104 and AZ7550. High-performance liquid chromatography and accelerator mass spectrometry were used to characterize IV dose PK. Geometric mean absolute oral bioavailability of osimertinib was 69.8% (90% confidence interval, 66.7, 72.9). Oral osimertinib was slowly absorbed (median time to maximum plasma concentration [t ] 7.0 hours). Following t , plasma concentrations fell in an apparent monophasic manner. IV clearance and volume of distribution were 16.8 L/h and 1285 L, respectively. Arithmetic mean elimination half-life estimates were 59.7, 52.6, and 72.6 hours for osimertinib, AZ5104, and AZ7550, respectively (oral dosing), and 54.9, 68.4, and 99.7 hours for [ C]osimertinib, [ C]AZ5104, and [ C]AZ7550, respectively (IV dosing). Oral osimertinib was well absorbed. Simultaneous IV and oral PK analysis proved useful for complete understanding of osimertinib PK and showed that the first-pass effect was minimal for osimertinib.

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The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib

Abstract: Osimertinib can be co-administered with CYP3A4 inhibitors, but strong CYP3A inducers should be avoided if possible.

Cited by 56 publications

References 49 publications

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics

Modulation of Fexofenadine Pharmacokinetics by Osimertinib in Patients With Advanced EGFR‐Mutated Non–Small Cell Lung Cancer

Absolute Bioavailability of Osimertinib in Healthy Adults

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