Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.

Two cases were presented describing a potential drug-drug interaction with paclitaxel in HIV-infected patients. Patient 1 started palliative chemotherapy consisting of carboplatin and paclitaxel on days 1, 8 and 15 in a 28 day cycle while receiving an antiretroviral regimen which included darunavir/ritonavir (800/100 mg once daily). The first dose was completed without complications and blood count was within acceptable range. Three days after receiving the second dose, the patient had to be hospitalized due to a severe neutropenic sepsis, caused by a non-resistant Escherichia coli. Despite administration of meropenem, the patient did not recover and passed away three days after admission.  Patient 2 was receiving an antiretroviral regimen which included lopinavir/ritonavir (800/200 mg once daily) when chemotherapy for breast cancer was started with a cycle consisting of paclitaxel (80 mg/m2) once weekly and both pertuzumab and trastuzumab every 3 weeks. After the second paclitaxel dose, the patient was hospitalized due to neutropenic fever and the third dose was cancelled. Cycle 2 was started 1 week later after blood counts returned to normal, with 75% of the original paclitaxel dose, and was fully completed. However, rehospitalization followed and blood counts showed development of a pancytopenia. Lopinavir/ritonavir was substituted for dolutegravir because of the suspected drug-drug interaction between lopinavir/ritonavir and paclitaxel. Two weeks after hospitalization, with blood counts returned to acceptable range, the third cycle was initiated with 50% paclitaxel dose reduction. The remaining paclitaxel cycles were successfully completed, at reduced dosages (fourth cycle at 50%, fifth and sixth cycle at 60% of the original dose), without recurrent pancytopenia. These cases provide a better understanding of the clinical relevance of the drug-drug interaction between paclitaxel and ritonavir and the authors strongly advise to avoid the combination of paclitaxel, or another taxane, with ritonavir.

Coadministration of paclitaxel and carboplatin was studied in people living with HIV receiving ritonavir-containing ARV regimens (n=6) or non-ritonavir-regimens (n=10). Patients received paclitaxel (175 mg/m2 via 1-hour infusion) and carboplatin (target AUC 6 via 30-minute infusion) intravenously every 3 weeks for a maximum of 6 cycles. The adverse event profile was consistent with the known toxicity profile and there no differences between the two groups. Pharmacokinetics of paclitaxel were determined on cycle 1 day 1 after the first dose of paclitaxel in two patients in the ritonavir group (AUC data available for only one patient) and in 4 patients in the non-ritonavir group. There was a trend for paclitaxel Cmax and AUC to be elevated in patients receiving ritonavir compared to those in the non-ritonavir group (Cmax 6.8 and 17.7 vs 4.7 ± 0.6µM; AUC 50.2 vs 22.8 ± 8.1 µM.h; 95% CI not given). Based on these very limited pharmacokinetic data, the authors state “Pharmacokinetic studies in 6 patients revealed no significant differences in Cmax or AUC for paclitaxel between the 2 cohorts.”.

Life-threatening toxicity was observed in two HIV-positive patients treated with ritonavir boosted PIs and paclitaxel 100 mg/m2. The first patient’s antiretroviral regimen included lopinavir/ritonavir. Two days after receiving paclitaxel, he developed myalgias and arthralgias and by day 8 was neutropenic and died of sepsis.  The second patient’s regimen was indinavir/ritonavir twice daily and he developed febrile neutropenia on day 7 after starting paclitaxel. A second course of paclitaxel resulted in profound cytopenia and total body alopecia. Subsequently, his paclitaxel dose was reduced to 60 mg/m2 and was tolerated for 6 cycles. Carefully monitoring of taxane doses and initial dose reductions should be considered in patients who are receiving HAART regimens that have the capacity to alter paclitaxel metabolism.