Pharmacokinetics of simultaneously administered antileishmanial and antiretroviral drugs. Ethiopia

Transcription

1 Pharmacokinetics of simultaneously administered antileishmanial and antiretroviral drugs in HIV/VL coinfected patients in Ethiopia Anke E. Kip, Séverine Blesson, Fabiana Alves, Robert Kimutai, Peninah Menza, Bewketu Mengesha, Jan H.M. Schellens, Jos H. Beijnen, Asrat Hailu, Ermias Diro, Thomas P.C. Dorlo

2 HIV-VL co-infection rates up to 20-40% in specific regions of Ethiopia 1 Pharmacokinetics of antileishmanial and antiretroviral drugs in simultaneous treatment of HIV-VL coinfected patients has never been studied Pharmacokinetic samples collected in clinical trial HIV/VL 0511 (NCT ) 1 Diro et al. (2014) Map from 2 Malaria Consortium (2010)

3 Male adult Ethiopian HIV co-infected VL patients received following therapies: Monotherapy N=10 Liposomal amphotericin B Combination therapy N=20 Liposomal amphotericin B + miltefosine L-AMB 40 mg/kg L-AMB 30 mg/kg 28-day 50 mg miltefosine bi-daily 28 Patient parasite positive, but clinically better after one cycle, receives another cycle of same regimen ( extended treatment )

4 Pharmacokinetic samples collected in clinical trial HIV/VL 0511 (NCT ) Drug concentrations determined using LC-MS/MS 3 Miltefosine/ARV (Efavirenz, nevirapine) in DBS Total amphotericin B (AMB) in plasma PK analysis in R with non- compartmental analysis 3 Kip et al. (2015)

5 AMB C max ~50% lower than previously observed 57.6 µg/ml in non-vl patients 4 4 Astellas. Product Monograph (2009).

6 Miltefosine exposure 35% lower compared to previously observed ~30,000 ng/ml C max of 18,700 ng/ml 5 Wasunna et al. (2016)

7 Significantly higher miltefosine exposure for NVP vs EFV-treated patients Higher miltefosine day 28 concentration for nevirapine (NVP) vs efavirenz (EFV)-treated patients (25,100 vs 18,000 ng/ml, p=0.04, two-sample t-test)

8 Conclusion Amphotericin B exposure 57% lower than previously observed in non-vl patients Possibly due to increased liposome clearance Miltefosine exposure 35% lower compared to previously observed ~30,000 ng/ml Partially explained by flat-fixed 100 mg dosing Higher dose to be considered in this patient population No profound effect of antileishmanial treatment on EFV/NVP exposure, exceptions on individual level

9 Acknowledgements 9 The patients who were willing to participate in this clinical trial Antoni van Leeuwenhoek hospital T.P.C. Dorlo J.H. Beijnen J.H.M. Schellens DNDi Africa P. Menza M. Wasunna R. Kimutai DNDi Africa data center DNDi Geneva S. Blesson F. Alves Department of Microbiology, Immunology, and Parasitology, Addis Ababa University, Ethiopia A. Hailu Department of Internal Medicine, University of Gondar, Gondar, Ethiopia E. Diro Clinical and laboratory clinical site Gondar B. Mengesha Leishmaniasis East Africa Platform (LEAP)

10 Funding statement This work was supported through DNDi by: Swiss Agency for Development and Cooperation, Switzerland Medicore Foundation, Liechtenstein Médecins Sans Frontières, International Department for International Development, United Kingdom; Dutch Ministry of Foreign Affairs, The Netherlands Federal Ministry of Education and Research through KfW, Germany The research leading to these results has received funding from the European Union Seventh Framework Programme under grant agreement n We thank Gilead for the donation of AmBisome.

11 Thank you for your attention

12 References Diro et al. (2014). Visceral Leishmaniasis and HIV coinfection in East Africa. PLoS Negl Trop Dis; 8(6): e Malaria Consortium (2010) Leishmaniasis control in eastern Africa: Past and present efforts and future needs. Situation and gap analysis. Available: VL%20EA%20Situation%20Analysis%20Fina_Janl.pdf. 3. Kip et al. (2015). Validation and Clinical Evaluation of a Novel Method To Measure Miltefosine in Leishmaniasis Patients Using Dried Blood Spot Sample Collection. Antimicrob Agents Chemother; 60(4): Astellas Pharma Canada Inc. Product Monograph Accessed 20 Dec Wasunna et al. (2016). Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial. PLoS Negl Trop Dis; 10(9): e

13 Objectives Provide first ever description of liposomal amphotericin B pharmacokinetics in VL patients Characterize PK of both liposomal amphotericin B and miltefosine in HIV co-infected VL patients Characterize PK of antiretroviral (ARV) drugs in VL co-infected HIV patients 1 2 3

14 No profound effect of antileishmanial treatment on efavirenz/nevirapine exposure Exceptions on individual patient level Efavirenz:

15 Demographics Parameter Total Monotherapy L-AMB Combination therapy L-AMB + MIL Total no. of patients Age (yr) 33 (27-45) 36 (27-45) 33 (28-44) Body weight day (kg) 47.0 ( ) 48.5 ( ) 46.5 ( ) Height (cm) 170 ( ) 170 ( ) 170 ( ) Treatment outcome after one treatment cycle Cure [no. (%)] 13 (43) 3 (30) 10 (50) Receive rescue treatment [no. (%)] 3 (10) 2 (20) 1 (5) Receive extended treatment [no. (%)] 14 (47) 5 (50) 9 (45) ART at end antileishmanial treatment [no. (%)] TDF-3TC-EFV (300/300/600 mg) 23 (77) 9 (90) 14 (70) Other treatments including EFV 2 (7) 2 (10) Other treatments including NVP 4 (13) 1 (10) 3 (15) Other treatments including LPV/r 1 (3) 1 (5)

16 Exposure-response relation antileishmanial drugs

17 Demographics Parameter Total Monotherapy L-AMB Combination therapy L-AMB + MIL Total no. of patients Age (yr) 33 (27-45) 36 (27-45) 33 (28-44) Body weight day (kg) 47.0 ( ) 48.5 ( ) 46.5 ( ) Height (cm) 170 ( ) 170 ( ) 170 ( ) Treatment outcome after one treatment cycle Cure [no. (%)] 13 (43) 3 (30) 10 (50) Receive rescue treatment [no. (%)] 3 (10) 2 (20) 1 (5) Receive extended treatment [no. (%)] 14 (47) 5 (50) 9 (45) Treatment outcome after two treatment cycles Cure [no. (%)] 9 (30) 1 (10) 8 (40) Rescue treatment [no. (%)] 5 (17) 4 (40) 1 (5) ART at start antileishmanial treatment [no. (%)] TDF-3TC-EFV (300/300/600mg) 15 (50) 7 (70) 8 (40) Other treatments including EFV 3 (10) 3 (15) Other treatments including NVP 4 (13) 1 (10) 3 (15) Other treatments including LPV/r 1 (3) 1 (5) No treatment 7 (23) 2 (20) 5 (25) ART at end antileishmanial treatment [no. (%)] TDF-3TC-EFV (300/300/600 mg) 23 (77) 9 (90) 14 (70) Other treatments including EFV 2 (7) 2 (10) Other treatments including NVP 4 (13) 1 (10) 3 (15) Other treatments including LPV/r 1 (3) 1 (5)