Mechanism of Action: Cytochrome P450 2B6 Inducers

Drugs with Mechanism of Action: Cytochrome P450 2B6 Inducers

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Exclusivity Expiration
Torrent Pharms	CARBAMAZEPINE	carbamazepine	TABLET, CHEWABLE;ORAL	075712-001	Jul 5, 2001	AB	RX	No	No
Amneal Pharms	CARBAMAZEPINE	carbamazepine	TABLET, EXTENDED RELEASE;ORAL	212704-002	Sep 22, 2023		DISCN	No	No
Taro Pharm Inds	CARBAMAZEPINE	carbamazepine	TABLET, CHEWABLE;ORAL	075687-001	Oct 24, 2000	AB	RX	No	No
Nostrum Labs Inc	CARBAMAZEPINE	carbamazepine	CAPSULE, EXTENDED RELEASE;ORAL	076697-001	May 20, 2011	AB	RX	No	No
Taro	CARBAMAZEPINE	carbamazepine	TABLET, EXTENDED RELEASE;ORAL	078115-002	Mar 31, 2009	AB	RX	No	No
Torrent Pharms	CARBAMAZEPINE	carbamazepine	TABLET;ORAL	077272-001	Dec 7, 2005		DISCN	No	No
Amneal Pharms	CARBAMAZEPINE	carbamazepine	TABLET, EXTENDED RELEASE;ORAL	212704-003	Sep 22, 2023		DISCN	No	No

rket Dynamics and Patent Landscape for Cytochrome P450 2B6 Inducers

The cytochrome P450 2B6 (CYP2B6) enzyme plays a critical role in metabolizing drugs such as antiretrovirals (efavirenz), antidepressants (bupropion), and chemotherapeutics (cyclophosphamide)[5][7]. Induction of CYP2B6 by drugs like phenobarbital, rifampin, and carbamazepine can lead to clinically significant drug-drug interactions (DDIs), affecting therapeutic outcomes[1][6][9]. Here’s a breakdown of the market dynamics and patent landscape:

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Market Dynamics

Therapeutic Areas and Key Drugs

• Antiretroviral Therapy: Efavirenz, a cornerstone of HIV treatment, is metabolized primarily by CYP2B6. Induction reduces its plasma concentration, risking therapeutic failure[6][9].
• Smoking Cessation: Bupropion, a CYP2B6 substrate, is used for nicotine dependence. Variability in CYP2B6 activity influences efficacy and adverse effects[1][3].
• Oncology: Cyclophosphamide requires CYP2B6-mediated activation. Induction alters cytotoxic metabolite levels, impacting chemotherapy outcomes[5][7].

Regulatory and Clinical Challenges

• FDA guidelines recommend assessing CYP2B6 induction risk during drug development[1][11].
• Current probe substrates (e.g., bupropion, efavirenz) lack selectivity due to co-induction of CYP3A4, complicating clinical DDI predictions[1][6].
• Demand for Predictive Tools: Physiologically based pharmacokinetic (PBPK) models (e.g., SimCYP) and machine learning platforms are being developed to improve DDI forecasts[10][6].

Genetic Variability and Personalized Medicine

• Polymorphisms in CYP2B6 (e.g., CYP2B66) affect drug metabolism across populations, driving demand for pharmacogenomic testing[3][7][9].
• Mayo Clinic and others offer clinical genotyping to guide dosing for drugs like methadone and nevirapine[3].

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Patent Landscape

Drug Development and Screening Technologies

• Assay Innovations: Patents like the P450-Glo™ CYP2B6 Assay (Promega) enable high-throughput screening for induction/inhibition, critical for early-stage drug discovery[13].
• Nicotine Metabolism Modulation: Patent US20090285797A1 describes methods to inhibit CYP2A6 and CYP2B6 to regulate nicotine-to-cotinine conversion, relevant for smoking cessation therapies[2].

Genetic Diagnostics

• Patent EP1272663A2 covers CYP2B6 polymorphisms linked to variable drug responses, emphasizing diagnostics for personalized dosing[12].

Therapeutic Targeting

• CYP2B6 Inhibitors/Inducers: While no strong clinical index inhibitors exist[11], rifampin (moderate inducer) and phenobarbital are reference inducers used in DDI studies[1][9].

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Competitive and Emerging Trends

• DDI Risk Mitigation: Companies prioritize drugs with lower CYP2B6 induction potential or combine therapies with enzyme inhibitors[9].
• AI/ML Integration: Machine learning models predict CYP2B6 inhibitors/substrates, accelerating drug discovery[10].
• Gene-Editing Tools: Research into CYP2B6 regulation (e.g., CAR/PXR nuclear receptors) may yield novel inducers or suppressors[5][9].

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Key Challenges

1. Lack of Selective Probes: Existing probes (efavirenz, bupropion) are confounded by CYP3A4 co-induction[1][6].
2. Genetic Diversity: Population-specific CYP2B6 variants necessitate tailored dosing strategies[7][9].
3. Regulatory Hurdles: FDA requirements for DDI studies drive R&D costs but improve drug safety profiles[11].

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Highlight

"Current methods and probe substrates preclude accurate prediction of CYP2B6 induction. Identification of a sensitive and selective clinical substrate for CYP2B6 [...] is needed."
— Evaluation of CYP2B6 Induction and Prediction of Clinical Drug Interactions[1][6].

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Future Outlook

• Next-Gen Probes: Development of CYP2B6-specific substrates (fraction metabolized >0.9) will enhance DDI prediction[1].
• Combo Therapies: Drugs leveraging CYP2B6 induction (e.g., cancer prodrugs) may gain traction with improved targeting.
• Global Health Impact: Optimizing antiretroviral dosing in populations with high CYP2B66 prevalence (e.g., African cohorts) could reduce HIV treatment failures[7][9].

This landscape underscores the interplay between genetic variability, regulatory demands, and innovation in drug development for CYP2B6-mediated therapies.

References

1. https://pubmed.ncbi.nlm.nih.gov/27422672/
2. https://patents.google.com/patent/US20090285797A1/en
3. https://www.mayocliniclabs.com/test-catalog/overview/610042
4. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=4bfa3719f62761a84fba1483e53ba41792590d61
5. https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2013.00024/full
6. https://pmc.ncbi.nlm.nih.gov/articles/PMC11024975/
7. https://pmc.ncbi.nlm.nih.gov/articles/PMC8313315/
8. https://pmc.ncbi.nlm.nih.gov/articles/PMC5979536/
9. https://pmc.ncbi.nlm.nih.gov/articles/PMC5045548/
10. https://pubmed.ncbi.nlm.nih.gov/37437120/
11. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
12. https://patents.google.com/patent/EP1272663A2/en
13. https://cdn.technologynetworks.com/TN/Resources/PDF/the-p450-glo-cyp2b6-assay-a-rapid-and-selective-assay-for-measuring-cyp2b6-induction-and-inhibition.pdf