Population pharmacokinetics and exposure-safety relationship of nanoliposomal irinotecan (MM-398, nal-IRI) in patients with solid tumors.

Background: MM-398 is a nanoliposomal irinotecan (nal-IRI). This study characterized the population PK and exposure–response with MM-398 in patients with solid tumors. Methods: Population PK analysis was performed for total irinotecan (IRI) and its active metabolite SN-38 in 353 patients administered MM-398 60-120 mg/m² in 6 studies. Covariates include body size (BSA), hepatic and renal functions (UGT1A1*28 7/7, bilirubin, liver metastasis, AST, ALT, albumin, CrCl), demographics (sex, race, age), and external factors (co-treatment with 5-FU, manufacturing site). Exposure-safety (neutropenia, diarrhea, and anemia) relationships were evaluated from 6 studies. Predictions of incidence rates of AEs were obtained from exposure-safety and predicted exposure with a dose of 80mg/m². Results: Population PK of IRI was described as a 2-compartmental model, and SN-38 as a 1-compartmental model. Significant covariates to IRI were race and BSA; covariates to SN-38 were baseline bilirubin and BSA. No other covariates were significant; association with UGT1A1*28 was not significant. Compared to 120 mg/m² q3w, MM398 80 mg/m² q2w had similar average (C_avg), and 1.5-fold lower C_max for both IRI and SN-38. SN-38 C_max was associated with incidence of G ≥ 3 neutropenia and anemia, and IRI C_max was associated with incidence of G ≥ 3 diarrhea. Compared to Caucasians, Asians had 0.5-fold lower IRI C_max, corresponding to 5% lower predicted G ≥ 3 diarrhea. In contrast, Asians had 1.5-fold higher SN-38 C_max than Caucasians, corresponding to 7% higher predicted G ≥ 3 neutropenia. Compared to patients with bilirubin < 1 mg/dL, patients with bilirubin 1-2 mg/dL had 1.4-fold higher SN-38.Conclusions: MM-398 at a lower dose, given more frequently, was predicted to have similar C_avg and lower C_max. IRI C_maxwas associated with diarrhea and SN-38 C_max was associated with neutropenia and anemia. Asians had lower IRI levels, but higher SN-38. Increasing baseline bilirubin was associated with higher SN-38 levels. Clinical trial information: NCT01494506

Citation:
J Clin Oncol 33, 2015 (suppl; abstr e13588)

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