3947 - Integrated population pharmacokinetic modelling of liposomal irinotecan in patients with various tumour types, including untreated metastatic pancreatic cancer (mPC)

Background

Liposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan which prolongs circulation of irinotecan and its active metabolite SN-38. This analysis describes the population pharmacokinetics (PK) of nal-IRI in patients with various tumour types, including untreated mPC.

Methods

Plasma concentration data for total irinotecan (tIRI) and SN-38 from an open-label, phase 2 study of nal-IRI plus 5-fluorouracil/leucovorin and oxaliplatin in patients with untreated mPC (NCT02551991; N = 48) were pooled with data from six other nal-IRI studies (five phase 1/2, one phase 3) in various tumour types. Data from overall 440 patients were used in the population PK model for tIRI and SN-38 after nal-IRI administration. PK parameters were estimated with non-linear mixed effects modelling. The adequacy of the model was assessed based on the uncertainty of parameter estimates, and on advanced evaluation methods such as visual predictive check. Potential covariates such as patient demographics and genotype were investigated to examine inter-individual variability.

Results

tIRI is described by a two-compartment model with first-order elimination. SN-38 is formed directly by a first-order constant from the central compartment of nal-IRI or after using a transit compartment. In the pooled population (N = 440), clearance was 0.1 L/h and 150 L/h for tIRI and SN-38, respectively. Central and peripheral volumes of distributions for tIRI were 4 L and 0.4 L, respectively. Consistent with previous data, tIRI clearance was 80% higher in patients of Asian ethnicity (n = 154/440) than other populations. Increasing bilirubin levels were associated with lower SN-38 clearance, and tIRI and SN-38 clearances were 20% lower in females than males. The UGT1A128 7/7 homozygous genotype (6% of the study population) had no statistically significant impact on SN-38 clearance. Model evaluation was satisfactory for both tIRI and SN-38.

Conclusions

The PK of nal-IRI and SN-38 in patients with mPC is well described by the population model. The results suggest that UGT status has no impact on the PK of nal-IRI.

Clinical trial identification

Editorial acknowledgement

Oxford PharmaGenesis, Oxford, UK for providing editorial support, which was sponsored by Ipsen, Abingdon, UK.

Legal entity responsible for the study

Ipsen.

Funding

Ipsen.

Disclosure

T. Macarulla: Honoraria (institution): Shire Pharmaceuticals; Honoraria (institution): Roche; Honoraria (institution): Tesaro; Honoraria (institution): Baxter; Honoraria (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (institution): Celgene; Honoraria (institution): QED Therapeutics; Honoraria (institution): Genzyme Europe; Honoraria (institution): Baxalta; Honoraria (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (institution): Incyte; Honoraria (institution): Genzyme; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: H3 Biomedicine. K. Brendel: Full / Part-time employment: Ipsen. Z.A. Wainberg: Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: Bayer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Ipsen. F. Dayyani: Advisory / Consultancy: Array; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Sirtex. B. Zhang: Full / Part-time employment: Ipsen. B. Belanger: Full / Parttime employment: Ipsen. Y. Moore: Full / Part-time employment: Ipsen. A. Pedret-Dunn: Full / Parttime employment: Ipsen. F. Maxwell: Full / Part-time employment: Ipsen. A. Dean: Advisory / Consultancy, Non-paid: Shire; Advisory / Consultancy, Non-paid: Specialised Therapeutics Australia; Travel / Accommodation / Expenses, Grant: Amgen. All other authors have declared no conflicts of interest.