Swati Jaiswal (1,2) Thomas PC Dorlo (3,4) Mahendra Shukla (1,2) Abhisheak Sharma (1,2,5) Brajendra Tiwari (6) Neena Goyal (6) and Jawahar Lal (1,2)
(1) Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, India (2)Academy of Scientific and Innovative Research, New Delhi, India (3) Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands (4) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden (5)Department of Pharmaceutics and Drug Delivery, The University of Mississippi, Mississippi, USA (6)Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow, India
Objectives: The knowledge about the exposure-effect relationship of miltefosine (MF) is limited, which is imperative for understanding the risk factors associated with its treatment failure [1,2]. Preclinical PK-PD evaluation of MF could be a decisive approach too and can be very useful if successfully translated to clinical outcomes. Therefore, a PK-PD study was planned in L. donovani infected hamster model.
Methods: Multiple dose oral (10, 20 and 30 mg/kg dose daily for 5 days at 24 hr interval) PD study of MF was carried out in L. donovani infected Golden Syrian hamsters. During PD study 1 pre-treatment and 4 post-treatment spleen biopsies were carried out on day 7, 14, 21 and 28 and % infection [(number of amastigotes/number of macrophage) *100] was recorded as PD parameter. Twenty infected hamster received no treatment and were used for modeling base line and natural disease progression. Multiple dose oral PK studies were carried out in healthy hamsters at similar doses (n=10 hamsters, per dose group). Blood samples were withdrawn up to 28 days post treatment and harvested plasma samples were analysed using LC-MS/MS [3]. The PK model was developed first and thereafter the PD model, using a sequential fit with fixed population PK parameters. Analysis was conducted using FOCE I in NONMEM 7.3.0. Xpose and PsN were used for graphical evaluation and model diagnostics.
Results: A one compartment model provided the best fit to the PK data. The estimated typical value for absorption rate constant (ka), oral clearance (CL/F) and oral volume of distribution (V/F) were 0.391 h-1(0.097), 0.012 L/h/kg (0.044) and 1.15 L/kg (0.037). BSV in CL/F and ka were modelled with an exponential error. BSV in ka and CL were estimated to be 32% and 11%, respectively. RUV was characterized by a proportional error model and found to be 30%. The final PK-PD model was composed of a base line model with proportional disease progression and an effect compartment-inhibitory sigmoidal Emax model with symptomatic drug effect. This model best described the data with adequate VPC and basic goodness of fit plots. The estimated value for baseline in terms of % infection is 15 and the disease progression rate (α) is 0.011 h-1. The estimated plasma EC50 for MF is 0.32 mg/L and maximum response (Emax) is 0.95 % (93 % reduction in baseline % infection value).
Conclusions: The final PK-PD model described the data well and can be used for studying drug effects in hamster from MF mono-therapy.
References:
[1] Sundar S, Singh A, Rai M, Prajapati VK, Singh AK, Ostyn B, Boelaert M, Dujardin JC, Chakravarty J. Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clin Infect Dis (2012) 55(4):543-50.
[2] Rijal S, Ostyn B, Uranw S, Rai K, Bhattarai NR, Dorlo TP, Beijnen JH, Vanaerschot M, Decuypere S, Dhakal SS, Das ML, Karki P, Singh R, Boelaert M, Dujardin JC. Increasing failure of miltefosine in the treatment of Kala-azar in Nepal. and the potential role of parasite drug resistance, reinfection, or noncompliance. Clin Infect Dis (2013) 56(11):1530-8
[3] Jaiswal S, Sharma A, Shukla M, Lal J. LC-coupled ESI MS for quantification of miltefosine in hamster and human plasma. Bioanalysis (2016): Accepted manuscript.
Reference: PAGE 25 (2016) Abstr 5945 [www.page-meeting.org/?abstract=5945]
Poster: Drug/Disease modeling - Infection