CYP Suppression in Human Hepatocytes by Monomethyl Auristatin E, the Payload in Brentuximab Vedotin (Adcetris®), is Associated with Microtubule Disruption

Wolenski, Francis S.; Xia, Cindy Q.; Ma, Bing-Li; Han, Tae Hyung; Shyu, Wen Chyi; Balani, Suresh K.

doi:10.1007/s13318-017-0455-5

Cited by 8 publications

(11 citation statements)

References 9 publications

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“…Effect of Abemaciclib on CYP1A2, 2C9, 2D6 and 3A4 Substrates (Wolenski et al, 2018). Despite the numerous examples of CYP downregulation in vitro, there is no clear example of CYP in vitro downregulation translating into meaningful DDIs in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

et al. 2020

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Abemaciclib is an orally administered, potent inhibitor of cyclindependent kinases 4 and 6 and is metabolized extensively by CYP3A4. The effects of abemaciclib on several CYPs were qualified in vitro and subsequently evaluated in a clinical study. In vitro, human hepatocytes were treated with vehicle, abemaciclib, or abemaciclib metabolites [N-desethylabemaciclib (M2) or hydroxyabemaciclib (M20)]. mRNA levels for eight CYPs were measured using reversetranscription quantitative polymerase chain reaction, and, additionally, catalytic activities for three CYPs were determined. In the clinical study, adult patients with cancer received a drug cocktail containing CYP substrates [midazolam (3A), warfarin (2C9), dextromethorphan (2D6), and caffeine (1A2)] either alone or in combination with abemaciclib. Plasma pharmacokinetics (PK) samples were analyzed for all substrates, caffeine metabolite paraxanthine, and abemaciclib; polymorphisms of CYP2C9, CYP2D6, CYP3A4, and CYP3A5 were evaluated. In vitro, downregulation of CYP mRNA, including 1A2, 2B6, 2C8, 2C9, 2D6, and 3A, by abemaciclib and/or M2 and M20 was observed at clinically relevant concentrations. In humans, abemaciclib did not affect the PK of CYP2D6 or CYP2C9 substrates. Minor statistically significant but clinically irrelevant changes were observed for midazolam [area under the concentration versus time curve from zero to infinity (AUC 0-inf) (13% lower), C max (15% lower)], caffeine [AUC 0-inf (56% higher)], and paraxanthine: caffeine [area under the concentration versus time curve from 0 to 24 hours ratio (was approximately 30% lower)]. However, given the magnitude of the effect, these changes are not considered clinically relevant. In conclusion, the downregulation of CYP mRNA mediated by abemaciclib in vitro did not translate into clinically meaningful drug-drug interactions in patients with cancer. SIGNIFICANCE STATEMENT Despite observations that abemaciclib alters the mRNA of various CYP isoforms in vitro, a clinical study using a drug cocktail approach found no clinically meaningful drug-drug interactions between abemaciclib and a range of CYP substrates [midazolam (CYP3A4), S-warfarin (CYP2C9), dextromethorphan (CYP2D6), and caffeine (CYP1A2)]. This lack of translation suggests greater understanding of mechanisms of CYP downregulation is needed to accurately predict clinical drug-drug interaction risk from in vitro data.

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Section: Discussionmentioning

confidence: 99%

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

et al. 2020

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“…It was found that MMAE exposure was approximately two times higher in patients with severe renal impairment (creatinine clearance < 30 mL/minute; ref. 175). Therefore, it is advisable to avoid the use of Brentuximab vedotin in patients with severe renal dysfunction.…”

Section: Metabolic Profilementioning

confidence: 99%

Antibody–Drug Conjugates: A Comprehensive Review

Khongorzul

Ling

Khan

et al. 2020

Molecular Cancer Research

570

447

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Antibody-drug conjugates (ADC) are one of the fastest growing anticancer drugs. This approach comprises a mAb conjugated to the cytotoxic payload via a chemical linker that directed toward a target antigen expressed on the cancer cell surface, reducing systemic exposure and therefore toxicity. ADCs are complex molecules that require careful attention to various components. Selection of an appropriate target, an mAb, cytotoxic payload, and the manner in which the antibody is linked to the payload are key determinants of the safety and efficacy of ADCs. This review provides an overview of the systemic evaluation of each component of an ADC design, improved understanding of the mechanism of action of ADC, and mechanistic pathways involved in ADC resistance and various strategies to optimize ADC design. Moreover, this review also shed light on the current status of ADCs that have gained regulatory approval from the FDA including a description of biology and chemistry, metabolic profiles, adverse events, drug interactions, and the future perspective on combination strategies with other agents, including immunotherapy.

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“…Severe renal impairment with creatinine clearance < 30 mL/min resulted in an increase of MMAE exposure by approximately two-fold. [ 33 ] In a pediatric population, exposures were approximately dose related, with a trend towards lower ADC exposures at lower ages/body weights. Median AUC in children and adolescents was approximately 14% and 3% lower than in adult patients, respectively, while MMAE exposures were 53% lower and 13% higher, respectively [ 34 ].…”

Section: Metabolic Profilementioning

confidence: 99%

“…Strong CYP3A4 and P-gp inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) were found to increase MMAE exposure by 73% but did not change the plasma exposure to BV. [ 33 ] Co-administration of BV with strong inhibitors may lead to increased incidence of neutropenia. Rifampicin, a strong CYP3A4 inducer, did not alter the plasma exposure to BV but reduced plasma concentrations of MMAE metabolites.…”

Section: Drug Interactionsmentioning

confidence: 99%

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Safety and Tolerability of Antibody-Drug Conjugates in Cancer

Wolska-Washer

Robak

2019

Drug Saf

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Antibody-drug conjugates are monoclonal antibodies attached to biologically active drugs through chemical linkers that deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. Currently, there are about 110 ongoing studies implementing antibody-drug conjugates in the treatment of multiple human malignancies. Antibody-drug conjugates carry a feature of the specificity of a monoclonal antibody and the anti-neoplastic potential of a cytotoxin. The first antibody-drug conjugate was approved in 2001, and the field of antibody-drug conjugates has expanded since then with three more antibody-drug conjugates being added to the market. The complex structure of the antibody-drug conjugate poses a challenge in designing a clinically adequate molecule. Antibody-drug conjugates are usually well tolerated with some predictable adverse reactions, as well as new medical issues, that need careful approach. This review provides an outline of the current status of the efficacy and safety of antibody-drug conjugates in malignant diseases.

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CYP Suppression in Human Hepatocytes by Monomethyl Auristatin E, the Payload in Brentuximab Vedotin (Adcetris®), is Associated with Microtubule Disruption

Cited by 8 publications

References 9 publications

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

Antibody–Drug Conjugates: A Comprehensive Review

Safety and Tolerability of Antibody-Drug Conjugates in Cancer

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