L01EX03 - Pazopanib |
Propably not porphyrinogenic |
PNP |
Rationale
Pazopanib is a major substrate of CYP3A4. It is a weak inhibitor of CYP3A4 in vivo.
Risk for gastrointestinal adverse events in the form of nausea and diarrhoea motivates vigilance against insufficient intake of food, especially of carbohydrate.
Chemical description
The sulphonamide moiety of the molecule is not directly coupled to a heterocycle, but to aminobenzene and this molecule is probably not porphyrinogenic.
Therapeutic characteristics
Pazopanib is indicated for advanced kidney cell cancer.
Very common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are nausea, vomiting, diarrhoea and abdominal pain.
Hepatic exposure
Significant
Metabolism and pharmacokinetics
Pazopanib is highly protein bound (> 99%) and is metabolized mainly by CYP3A4 with minor metabolism by CYP1A2 and CYP2C8. It is a weak inhibitor of CYP3A4, CYP2C8 and CYP2D6 (Keisner 2011, Tan 2010). The half-life elimination is approximately 31 hours.
In vitro studies have shown that pazopanib inhibit CYP1A2, 3A4, 2B6, 2C8, 2C9, 2C19 and 2E1, and induce CYP3A4 (SPC). Clinical studies with caffeine, a CYP1A2 substrate, and omeprazole, a CYP2C19 substrate, showed that pazopanib had no relevant effect on the pharmacokinetics of the substrates (SPC). This indicates that pazopanib does not induce or inhibit CYP1A2 or CYP2C19.
An in vivo study has shown that co-administration of pazopanib with paclitaxtel, a CYP3A4 and CYP2C8 substrate, increased the plasma concentration of paclitaxel by 26%. This indicates that pazopanib may be a weak inhibitor of CYP3A4 or CYP2C8, or both (SPC, Tan 2010 and van Geel 2012).
Pazopanib also increased the mean AUC of midazolam, a CYP3A4 substrate, by 30% which indicates that it is an inhibitor of CYP3A4 (SPC). In vitro data indicates that pazopanib is a mechanism-based inhibitor of CYP3A4 (Kenny 2012).
References
- Scientific articles
- Keisner SV, Shah SR. Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma. Drugs. 2011 Mar 5;71(4):443-54. PMID 21395357. #3051
- Kenny JR, Mukadam S et al. Drug-drug interaction potential of marketed oncology drugs: in vitro assessment of time-dependent cytochrome P450 inhibition, reactive metabolite formation and drug-drug interaction prediction. Pharm Res. 2012 Jul;29(7):1960-76. PMID 22415140. #3049
- Tan AR, Dowlati A et al. Phase I study of pazopanib in combination with weekly paclitaxel in patients with advanced solid tumors. Oncologist. 2010;15(12):1253-61. PMID 21147873. #3053
- van Geel RM, Beijnen JH et al. Concise drug review: pazopanib and axitinib. Oncologist. 2012;17(8):1081-9. PMID 22733795. #4741
- Drug reference publications
- Up to date. Pazopanib. #3055
- Summary of Product Characteristics
- Norwegian medicines agency. Summary of Product Characteristics (SPC). Pazopanib. #3052
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