Thomas P.C. Dorlo (1), Fabiana Alves (2), Elin M. Svensson (3), Jan H.M. Schellens (1,4), Alwin D.R. Huitema (4)
(1) Utrecht University, Utrecht, The Netherlands, (2) Drugs for Neglected Diseases initiative, Geneva, Switzerland, (3) Uppsala University, Uppsala, Sweden, (4) Netherlands Cancer Institute, Amsterdam, The Netherlands
Objectives: We have previously shown that children treated with miltefosine for the neglected tropical parasitic disease visceral leishmaniasis (VL) are underexposed [1,2]. We therefore developed an allometric dosing regimen for children resulting in a similar drug exposure in children as adults [3]. A new exploratory pediatric clinical trial in East African VL patients is being designed to evaluate and validate this new dosing algorithm. This work aimed to provide estimates of a minimal sample size with sufficient power to evaluate clinically relevant PK parameters of the proposed allometric dosing algorithm for miltefosine in pediatric patients with VL in East Africa.
Methods: Anthropometric data from East-African VL patients were obtained from a previous clinical trial; total n=956 of whom n=454 pediatric (2-12 years). Miltefosine PK data for the targeted age group (2-12 years) were not available and concentration-time curves for the allometric dosing regimen (28 days) were therefore simulated using a well-established 2-compartment population PK model [1,3,4] and NONMEM 7.2. Secondary PK parameters (e.g. AUC, Time>EC50, Time>EC90) were derived. The Monte Carlo confidence interval approach was used to evaluate achieved power for various sample sizes [5]. Clinical trials (n=1000) were simulated with a random sample of patients (n=10, 15, 20,etc.) drawn from the anthropometric database available. The power to estimate the confidence intervals (95%CI) of the mean secondary PK parameters within precision intervals (15% or 20% precision) of the population mean was assessed.
Results: For AUC, the sample size minimally required to estimate the 95%CI within a 15% precision level (85%-118%) with a power of 0.95 was 25. For Time>EC50 and similar assumptions this was also 25. For Time>EC90 the sample size required to estimate 95%CI within a 20% precision level (power of 0.95) was >50. With a sample size of 25 the power to estimate the Time>EC90 95%CI within 20% precision level was 0.53.
Conclusions: Application of the Monte Carlo confidence interval approach yielded rational and pragmatic estimates of required sample sizes to assess miltefosine pediatric drug exposure for a novel dosing algorithm and enabled optimization of a planned pediatric population PK trial of miltefosine for VL in East Africa.
References:
[1] Dorlo TP, Rijal S, Ostyn B, de Vries PJ, Singh R, Bhattarai N, Uranw S, Dujardin JC, Boelaert M, Beijnen JH, Huitema AD. Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure. J Infect Dis. 2014; in press.
[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] Dorlo TP, Huitema AD, Beijnen JH, de Vries PJ. Optimal dosing of miltefosine in children and adults with visceral leishmaniasis. Antimicrob Agents Chemother. 2012;56(7):3864-72.
[4] 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. Antimicrob Agents Chemother. 2008;52(8):2855-60.
[5] Ogungbenro K, Aarons L. How many subjects are necessary for population pharmacokinetic experiments? Confidence interval approach. Eur J Clin Pharmacol. 2008;64(7):705-13.
Reference: PAGE 23 (2014) Abstr 3236 [www.page-meeting.org/?abstract=3236]
Poster: Methodology - Study Design