Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive cover after use of miltefosine for the treatment of visceral leishmaniasis
Thomas P.C. Dorlo (1, 2), Manica Balasegaram (3), María Angeles Lima (4), Peter J. de Vries (1), Jos H. Beijnen (2), Alwin D.R. Huitema (2)
(1) Division Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; (2) Department Pharmacy & Pharmacology, Slotervaart Hospital / the Netherlands Cancer Institute, Amsterdam, the Netherlands; (3) Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland; (4) Médecins Sans Frontières, Operational Centre Barcelona-Athens (MSF-OCBA), Barcelona, Spain
Background & Objectives: Miltefosine is currently the only oral drug available for the treatment of visceral leishmaniasis (VL), a neglected tropical parasitic infection. It has been adopted in national VL elimination programmes in India, Bangladesh and Nepal, but its widespread use and roll-out into rural clinics is severely hampered by its potential teratogenicity [1]. Foeto- and embryotoxicity have been shown in rabbits and rats. Therefore, use during pregnancy is strictly dismissed and contraceptive cover both during and after treatment is recommended in women of child-bearing potential.
Duration of post-treatment contraceptive cover in females remains a point of debate: most guidelines recommend either 2 or 3 months of post-treatment contraceptive cover, based on simple extrapolations of the initial elimination half-life [2]. However, miltefosine can be detected in plasma until at least 5 months post-treatment and the post-treatment contraceptive cover period could be extended accordingly [3]. Currently, various shortened miltefosine regimens for VL are being evaluated [4]. Nevertheless, uncertainty about the length of contraception to use for these shorter regimens strongly impedes their implementation. Unfortunately, previous pharmacokinetic (PK) data are not available for women of child-bearing potential because of exclusion from previous clinical trials.
This study aimed at providing a more scientific and rational approach to suggest durations of contraceptive cover after the use of various miltefosine regimens based on conversion and translation of dosing data from preclinical reproductive toxicity studies in animals and simulation of human PK data using a unique comprehensive anthropometric dataset of an historical cohort of Indian VL patients.
Methods: Anthropometric data for female VL patients of child-bearing potential were selected from a large demographic dataset from Médecins Sans Frontières (MSF dataset), collected between 2007 and 2009 from Vaishali District, Bihar State, India.
Simulations and estimations were performed using NONMEM VII and R. An open two-compartment model with first-order absorption and elimination from the central compartment, estimated and validated from previous miltefosine PK data [5], was used for Monte Carlo simulations. To account for body size, allometric scaling of clearance (0.75) and volume of distribution (1) by fat-free mass was applied, which was previously evaluated over a wide range of body sizes [5]. Concentration-time curves after miltefosine treatment for 5, 7, 10 & 28 days (2.5 mg/kg/day) were simulated using the demographic data from the MSF dataset (n=465). Simulations were repeated 100 times.
The no observed adverse effect level (NOAEL) of miltefosine in animal reproductive toxicity studies was determined from available literature. This NOAEL in rats was translated to a total human dose equivalent using available anthropometric data and Boyd’s formula for body surface area [6]. A human reproductive safety threshold exposure limit (RSTEL) for miltefosine was defined as the median predicted miltefosine exposure (AUC0-∞) following administration of the NOAEL human dose equivalent in Indian females of child-bearing potential. To account for any unknown between-species differences in sensitivity to reproductive toxicity, the RSTEL was divided by a default animal-to-human uncertainty factor of 10 [7].
The ‘unprotected’ residual exposure to miltefosine after end of the post-treatment contraceptive cover period (EOC) until infinity (AUCEOC-∞) was determined in the individual simulated PK curves for the different miltefosine regimens. Different periods of post-treatment contraceptive cover were considered (1, 2, 3 and 4 months). The individual AUCEOC-∞ was compared to the RSTEL and the probability for simulated Indian female VL patients of child-bearing potential of having an exposure exceeding the RSTEL was calculated.
Results: PK data were simulated for 465 selected treated Indian female VL patients of child-bearing potential with a median (IQR) age, weight and BMI of 25 (16-31) yrs, 38 (34-42) kg and 17.3 (15.8-18.8) kg/m2, respectively. The median (90% PI) times until the simulated plasma PK curves reached the current lower limit of quantitation (LLOQ; 4 ng/mL [8]) were 158 days (103-216 days), 176 days (119-235 days), 196 days (139-255 days) and 258 days (201-318 days), for the 5, 7, 10 and 28 day miltefosine regimen, respectively.
The NOAEL miltefosine dose in rats (0.6 mg/kg/day p.o. for 10 days [2]) corresponds with a total dose of 35.42 mg/m2 in rats, which was converted to a total human dose equivalent of 45 mg. The median (90% PI) simulated AUC0-∞ following administration of this dose in the selected Indian female VL patients was 245 µg*day/mL (140-467 µg*day/mL). Applying an animal-to-human safety factor of 10, a human RSTEL was derived of 24.5 µg*day/mL.
Median (90% PI) ‘unprotected’ miltefosine exposure after the end of contraception use (AUCEOC-∞) was e.g. for the 28 day regimen 54.50 (22.92-125.74), 8.74 (3.08-25.19), 4.11 (1.37-12.52) for 1, 2 and 3 months contraception, respectively. Probability of 'unprotected' supra-threshold (>RSTEL; >24.5 µg*day/mL) miltefosine exposure was very low (<0.2%) for a post-treatment contraceptive cover period of 4 months for the standard 28 day regimen and 2 months for the 5, 7 and 10 day miltefosine regimen. One month post-treatment contraception resulted in substantial probability of >RSTEL exposure for all regimens: 4.30%, 18.2%, 54.6% and 93.6%, for the 5, 7, 10 and 28 day regimen, respectively. The currently advised 2 months contraception (28 day regimen) led to 5.42% probability of having >RSTEL miltefosine exposure.
Discussion & Conclusion: The design of clinical teratogenic risk management-programs for drugs exhibiting reproductive toxicity in preclinical studies is problematic. Finding the optimal contraceptive cover is ethically imperative: too long a period may be economically not favourable and lead to adherence problems, while too short a period may increase the risk at congenital malformations. Recommended periods of post-treatment contraception are often based on the bioanalytical LLOQ, lacking any rational physiological and PK considerations. To our knowledge, this is the first study providing rational suggestions for contraceptive cover for a teratogenic drug based on animal-to-human dose conversion. To assess adequacy of contraceptive cover the probability of post-contraceptive supra-threshold miltefosine exposure was linked to the environmentally induced fraction of overall congenital malformation incidence (~0.2%) [9,10]. Our results indicate that, for the standard 28 day miltefosine regimen, post-treatment contraceptive cover may be extended from the currently advised 2 months to a period of 4 months. For the shortened regimens, 2 months may be sufficient, which has important implications for the implementation of these regimens in the developing world.
References:
[1] Berman J, Bryceson AD, Croft S, Engel J, Gutteridge W, Karbwang J, Sindermann H, Soto J, Sundar S, Urbina JA. Miltefosine: issues to be addressed in the future.Transactions of the Royal Society of Tropical Medicine & Hygiene. 2006; 100 Suppl 1: S41-4.
[2] Sindermann H, Engel J. Development of miltefosine as an oral treatment for leishmaniasis. Transactions of the Royal Society for Tropical Medicine & Hygiene 2006; 100 Suppl 1: S17-20.
[3] Dorlo TP, van Thiel PP, Huitema AD, Keizer RJ, de Vries HJ, Beijnen JH, de Vries PJ. Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients. Antimicrobial Agents and Chemotherapy 2008; 52: 2855-60.
[4] ClinicalTrials.gov. Phase III, Study of Three Short Course Combination Regimens (Ambisome®, Miltefosine, Paromomycin) Compared With AmBisome® Alone for the Treatment of Visceral Leishmaniasis in Bangladesh. 2011. Available at: http://clinicaltrials.gov/ct2/show/NCT01122771. Accessed 16 January 2012.
[5] Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB Journal 2008; 22: 659-661.
[6] U.S. Food and Drug Administration (FDA). Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. 2005. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078932.pdf. Accessed 16 January 2012.
[7] Dorlo TP, Huitema AD, Beijnen JH, de Vries PJ. Optimal Dosing of Miltefosine in Children and Adults with Visceral Leishmaniasis. Under review.
[8] Dorlo TP, Hillebrand MJ, Rosing H, Eggelte TA, de Vries PJ, Beijnen JH. Development and validation of a quantitative assay for the measurement of miltefosine in human plasma by liquid chromatography-tandem mass spectrometry. Journal of Chromatography B 2008; 865: 55-62.
[9] EURO-PERISTAT Project, with SCPE, EUROCAT, EURONEOSTAT. European Perinatal Health Report. 2008. Available at: http://www.europeristat.com/bm.doc/european-perinatal-health-report.pdf. Accessed 16 January 2012.
[10] European Surveillance of Congenital Anomalies (EUROCAT). Special Report: A Review of Environmental Risk Factors for Congenital Anomalies. 2004. Available at: http://www.eurocat-network.eu/content/Special-Report-Env-Risk-I-and-II.pdf. Accessed 17 January 2012.
