1602P - Pharmacokinetics (PK) of oral etoposide (OE) in Kenyans with HIV-related Kaposi's sarcoma (KS) on anti-retroviral therapy (ART)

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Cancer in Special Situations
Sarcoma
Presenter Robert Strother
Citation Annals of Oncology (2014) 25 (suppl_4): iv546-iv563. 10.1093/annonc/mdu358
Authors R.M. Strother1, N. Busakhala2, E. Njiru3, D. Jones4, A. Masters4, P. Loehrer5
  • 1Oncology, Christchurch Hospital, 8140 - Christchurch/NZ
  • 2Oncology, Moi University, Eldoret/KE
  • 3Oncology, Moi Teaching and Referral Hospital, Eldoret/KE
  • 4Clinical Pharmacology, Indiana University School of Medicine, Indianapolis/US
  • 5Oncology, IU Simon Cancer Center, Indianapolis/US

Abstract

Aim

Recent trials in SSA have shown OE is effective for palliation of KS symptoms, in patients without access to ART. OE PK exhibit high intersubject variability, and the dose-limiting side effect of OE, neutropenia, is related to etoposide exposure. The clinical risk of neutropenia is significantly higher in resource-limited settings, where access to supportive care may be limited. To date, the PK of OE in SSA populations has not been described; therefore the safety of OE is poorly defined. This trial describes first-dose PK of OE in Kenyan patients with HIV-related KS on ART.

Methods

This clinical trial was IRB approved. HIV-positive adults (≥18 yo) with biopsy-proven KS, without prior KS therapy, but on ART were eligible for participation. Following informed consent, patients were given 50 mg oral etoposide (IV formulation), with collection of dried blood spots for subsequent PK analysis at pre-dose, 1, 2, 4, 6, and 8 hours post-dose. Following liquid extraction of the dried blood spots, etoposide concentrations were measured using a validated HPLC-MS/MS assay with teniposide as internal standard. Non-compartmental PK analysis was performed using the linear trapezoidal rule in MS-Excel.

Results

29 subjects participated in this clinical trial. Day 1 PK parameters are presented. Patients were on several different ART regimens, although none were on ritonavir, a known strong inhibitor of etoposide metabolism.

PK Parameters of OE
PK Parameter Mean Coefficient of Variation (CV%) Range
Cmax (ng/mL) 611.7 36 114-1001
Tmax (h) 1.2 35 874-14760
AUC (0-inf) (ng/L.h) 3998 70 874-14760
CL/F (L/h) 18.25 64 3.39-57.21
Vd (L) 107 69 50-420

Conclusions

This study is the first to describe the PK of OE in Kenyans with HIV-associated KS on ART. While OE has exhibited high intersubject variability in prior studies, this study showed higher variability than previously reported: CV% in prior reports has generally been less than 50%, and in the present study is 60-70%. Ongoing analysis is exploring the role, if any, of body composition, co-medications, and genetics on the described PK variability. This preliminary data demonstrates that OE in a SSA population exhibits high intersubject variability, and therefore to ensure safety in this population, further study is needed of etoposide kinetics.

Disclosure

All authors have declared no conflicts of interest.