Pharmacokinetics of simultaneously administered antileishmanial and antiretroviral drugs in HIV/VL co- infected 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
WorldLeish 2017 HIV-VL co-infection rates up to 20-40% in specific regions of Ethiopia1
• Pharmacokinetics of antileishmanial and antiretroviral drugs in simultaneous treatment of HIV-VL co- infected patients has never been studied • Pharmacokinetic samples collected in clinical trial HIV/VL 0511 (NCT02011958)
Intro Methods Results Conclusion
1 Diro et al. (2014) WorldLeish 2017 Map from 2Malaria Consortium (2010) Male adult Ethiopian HIV co-infected VL patients received following therapies:
Monotherapy 1 2 3 4 5 10 17 24 N=10 Liposomal amphotericin B L-AMB 40 mg/kg
Combination 1 3 5 7 9 11 therapy N=20 28 Liposomal L-AMB 30 mg/kg amphotericin B + 28-day 50 mg miltefosine bi-daily miltefosine
Patient parasite positive, but clinically better after one cycle, receives another cycle of same regimen (“extended treatment”)
Intro Methods Results Conclusion
WorldLeish 2017 Pharmacokinetic samples collected in clinical trial HIV/VL 0511 (NCT02011958)
• 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
Intro Methods Results Conclusion
3Kip et al. (2015) WorldLeish 2017 AMB Cmax ~50% lower than previously observed 57.6 µg/mL in non-VL patients4
Intro Methods Results Conclusion
4Astellas. Product Monograph (2009). WorldLeish 2017 Miltefosine exposure 35% lower compared to previously observed ~30,000 ng/mL
Cmax of 18,700 ng/mL
Intro Methods Results Conclusion
5Wasunna et al. (2016) WorldLeish 2017 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)
Intro Methods Results Conclusion
WorldLeish 2017 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
Intro Methods Results Conclusion
WorldLeish 2017 Acknowledgements 9
The patients who were willing to participate Department of Microbiology, Immunology, and in this clinical trial Parasitology, Addis Ababa University, Ethiopia A. Hailu Antoni van Leeuwenhoek hospital T.P.C. Dorlo
J.H. Beijnen Department of Internal Medicine, University of J.H.M. Schellens Gondar, Gondar, Ethiopia
E. Diro DNDi Africa
P. Menza M. Wasunna Clinical and laboratory clinical site Gondar R. Kimutai B. Mengesha DNDi Africa data center DNDi Geneva Leishmaniasis East Africa S. Blesson Platform (LEAP) F. Alves
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°305178.
We thank Gilead for the donation of AmBisome®.
Thank you for your attention References
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1. Diro et al. (2014). Visceral Leishmaniasis and HIV coinfection in East Africa. PLoS Negl Trop Dis; 8(6): e2869 2. Malaria Consortium (2010) Leishmaniasis control in eastern Africa: Past and present efforts and future needs. Situation and gap analysis. Available: http://www.malariaconsortium.org/userfiles/file/NTD%20Resources/ 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): 2081-9 4. Astellas Pharma Canada Inc. Product Monograph. 2009. http://www.astellas.ca/pdf/en/monograph/2009-03-07. Accessed 20 Dec 2016. 5. 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): e0004880
Objectives
1• Provide first ever description of liposomal amphotericin B pharmacokinetics in VL patients 2• Characterize PK of both liposomal amphotericin B and miltefosine in HIV co-infected VL patients 3• Characterize PK of antiretroviral (ARV) drugs in VL co-infected HIV patients
Intro Methods Results Conclusion
WorldLeish 2017 No profound effect of antileishmanial treatment on efavirenz/nevirapine exposure
• Exceptions on individual patient level • Efavirenz:
Intro Methods Results Conclusion
WorldLeish 2017 Demographics
Total Monotherapy Combination therapy Parameter L-AMB L-AMB + MIL
Total no. of patients 30 10 20 Age (yr) 33 (27-45) 36 (27-45) 33 (28-44) Body weight day (kg) 47.0 (36.0-73.0) 48.5 (41.5-67.0) 46.5 (36.0-73.0) Height (cm) 170 (158-180) 170 (158-180) 170 (159-180) 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)
Intro Methods Results Conclusion
WorldLeish 2017 Exposure-response relation antileishmanial drugs
Demographics
Total Monotherapy Combination therapy Parameter L-AMB L-AMB + MIL
Total no. of patients 30 10 20 Age (yr) 33 (27-45) 36 (27-45) 33 (28-44) Body weight day (kg) 47.0 (36.0-73.0) 48.5 (41.5-67.0) 46.5 (36.0-73.0) Height (cm) 170 (158-180) 170 (158-180) 170 (159-180) 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)
Intro Methods Results Conclusion