From the Journals

‘Optimal’ pazopanib levels linked to lower toxicity in RCC patients



In patients with renal cell carcinoma, trough concentrations of pazopanib in a specific target range were associated with better safety and comparable efficacy, versus higher concentrations of the drug, authors of an exploratory investigation have reported.

Fewer serious toxicities were seen in patients with pazopanib concentrations in the 20- to 50-mcg/mL range, yet overall response rate was similar compared to patients with concentrations over 50 mcg/mL, according to results of the retrospective study.

The findings suggest therapeutic drug monitoring to achieve a specific trough concentration may be useful to optimize pazopanib dosing, according to investigator Tomohiro Terada, PhD, of Shiga University of Medical Science Hospital, Japan, and coinvestigators.

Therapeutic drug monitoring for sunitinib in RCC patients was recently covered by medical insurance in Japan, Dr. Terada and colleagues wrote in Clinical Genitourinary Cancer.

The strategy may be especially suited to adjusting the dose of pazopanib, which is often associated with severe toxicities and has pharmacokinetics that suggest a wide variation between individuals, they added.

The retrospective study by Dr. Terada and colleagues included 27 renal cell carcinoma patients who received pazopanib at doses of 400, 600, or 800 mg daily based on the recommendation of the treating physician, with doses reduced or discontinued based on adverse events or progression.

Trough concentrations of pazopanib 3 months after starting the treatment ranged from a low of 10.6 mcg/mL to a high of 106 mcg/mL, with a median of 49.1 mcg/mL, according to the report.

One-third of patients experienced grade 3 or greater toxicities, including anorexia, hypertension, anemia, and thrombocytopenia, among others. The median pazopanib concentration for those nine patients was 69.3 mcg/mL, compared with 41.2 mcg/mL for those not experiencing serious toxicities (P less than .05).

A concentration over 50.3 mcg/mL predicted grade 3 or greater toxicity, statistical analysis showed, with 8 out of 13 patients with concentrations above that threshold experiencing serious toxicities. By contrast, 1 of 14 patients below that threshold experienced grade 3 or greater toxicities.

No responses were observed in three patients with pazopanib concentrations below 20.5 mcg/mL, a concentration level considered to be subtherapeutic based on previous investigations.

Overall response rates were similar for patients with concentrations in the “optimal” 20.5- and 50.3-mcg/mL range and those with concentrations over 50.3 mcg/mL, according to the investigators.

Among 11 patients in that “optimal” range, partial responses were seen in 5, they reported, while for the 13 patients with high concentrations of the drug, partial responses were seen in 4 patients and a complete response was seen in 1 patient.

Trough concentrations may not predict all types of toxicities, according to the investigators, who said that the results of their small, retrospective analysis should be validated in a large, prospective study.

In particular, there was no significant relationship between trough concentration of pazopanib and development of grade 2 or greater hepatotoxicity, a common and specific side effect of the drug.

“Based on these findings, pazopanib-induced hepatotoxicity may not be related to the pharmacokinetics of pazopanib,” they wrote. “Therefore, pharmacogenomics testing is needed to predict pazopanib-induced hepatotoxicity.”

Dr. Terada and coauthors said they had no conflicts of interest to report.

SOURCE: Noda S et al. Clin Genitourin Cancer. 2018 Dec 7. doi: 10.1016/j.clgc.2018.12.001.

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