Relative Bioavailability of Orally Dispersible Tablet Formulations of Levo- and Racemic Praziquantel: Two Phase I Studies

Wilhelmina Maria Bagchus, Deon Bezuidenhout, Eleanor Harrison-Moench, Elly Kourany-Lefoll, Peter Wolna, Oezkan Yalkinoglu, Wilhelmina Maria Bagchus, Deon Bezuidenhout, Eleanor Harrison-Moench, Elly Kourany-Lefoll, Peter Wolna, Oezkan Yalkinoglu

Abstract

Orally dispersible tablet (ODT) formulations of levo praziquantel (L-PZQ) and racemic PZQ (rac-PZQ) are being developed to treat schistosomiasis in preschool-aged children. Two crossover studies (N = 32 and 36, respectively) assessed the relative bioavailability of these ODTs vs. Cysticide in adults. Bioavailability for L-PZQ of ODT rac-PZQ and Cysticide at 40 mg/kg was comparable (L-PZQ area under the concentration-time curve from zero to infinity (AUC0-∞ ) test/reference ratio (90% confidence interval (CI)): 96% (84-111%)), whereas relative bioavailability of ODT L-PZQ 20 mg/kg was ~40% that of Cysticide 40 mg/kg (test/reference: 40% (35-46%)). AUC0-∞ and peak plasma concentration (Cmax ) were highly variable in both studies. For both ODTs, L-PZQ AUC0-∞ showed greater than dose-proportional increase over the ranges tested and a significant food effect. Safety was comparable among formulations. The lower bioavailability of ODT L-PZQ, as well as the high variability and nondose-proportionality of pharmacokinetic (PK) parameters, highlighted the need for a dedicated pediatric dose-finding study for the selection of the most appropriate formulation and dose (L-PZQ ODT or rac-PZQ ODT).

Trial registration: ClinicalTrials.gov NCT02352713 NCT02271984.

© 2018 Merck KGaA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Study design and subject disposition. ODT, orally dispersible tablet.
Figure 2
Figure 2
Mean concentration‐time profiles of Levo‐praziquantel (L‐PZQ), dextro‐PZQ (D‐PZQ), and total racemate PZQ after administration of orally dispersible tablet (ODT) racemic PZQ (rac‐PZQ; EMR200585 001), ODT L‐PZQ (EMR200661 001), or Cysticide (both studies; pharmacokinetic populations, linear scale).
Figure 3
Figure 3
Plasma concentration‐time profiles for levo‐praziquantel by treatment, linear scale (EMR 200585 001 and EMR 200661‐001, pharmacokinetic populations).
Figure 4
Figure 4
Mean concentration‐time profile of Levo‐praziquantel (L‐PZQ) after administration of orally dispersible tablet (ODT) L‐PZQ or Cysticide (EMR 200661‐001, pharmacokinetic population; linear scale).

References

    1. Wu, G.Y. & Halim, M.H. Schistosomiasis: progress and problems. World J. Gasteroenterol. 6, 12–19 (2000).
    1. World Health Organization [Internet] . World Health Organization, Geneva, c2016. Fact Sheet No. 115: Schistosomiasis. [about 6 screens]. <> (2016). Accessed 6 December 2016.
    1. Colley, D.G. , Bustinduy, A.L. , Secor, W.E. , King, C.H. Human schistosomiasis. Lancet 383, 2253–2264 (2014).
    1. World Health Organization [Internet] . World Health Organization, Geneva, c2016. Schistosomiasis: Strategy. <> (2017) Accessed 17 February 2017.
    1. World Health Organization . Report of a meeting to review the results of studies on the treatment of schistosomiasis in preschool‐age children. 32 (World Health Organization, Geneva, 2011). <>.
    1. Allen, H.E. , Crompton, D.W. , de Silva, N. , LoVerde, P.T. & Olds, G.R. New policies for using anthelmintics in high risk groups. Trends Parasitol. 18, 381–382 (2002).
    1. Geary, T.G. et al Unresolved issues in anthelmintic pharmacology for helminthiases of humans. Int. J. Parasitol. 40, 1–13 (2010).
    1. Mafiana, C.F. , Ekpo, U.F. & Ojo, D.A. Urinary schistosomiasis in preschool children in settlements around Oyan Reservoir in Ogun State, Nigeria: implications for control. Trop. Med. Int. Health 8, 78–82 (2003).
    1. Opara, K.N. , Udoidung, N.I. & Ukpong, I.G. Genitourinary schistosomiasis among pre‐primary schoolchildren in a rural community within the Cross River Basin, Nigeria. J. Helminthol. 81, 393–397 (2007).
    1. Ekpo, U.F. , Laja‐Deile, A. , Oluwole, A.S. , Sam‐Wobo, S.O. & Mafiana, C.F. Urinary schistosomiasis among preschool children in a rural community near Abeokuta, Nigeria. Parasit. Vectors 3, 58 (2010).
    1. Bosompem, K.M. et al Infant schistosomiasis in Ghana: A survey in an irrigation community. Trop. Med. Int. Health 9, 917–922 (2004).
    1. Odogwu, S.E. et al Schistosoma mansoni in infants (aged <3 years) along the Ugandan shoreline of Lake Victoria. Ann. Trop. Med. Parasitol. 100, 315–326 (2006).
    1. World Health Organization . Prevention and control of schistosomiasis and soil‐transmitted helminthiasis: report of a WHO expert committee. (WHO Technical Report Series No. 912) p. 63 (World Health Organization, Geneva, Switzerland, 2002). <>.
    1. Coulibaly, J.T. , Panic, G. , Silué, K.D. , Kovacˇ, J. , Hattendorf, J. & Keiser, J. Efficacy and safety of praziquantel in preschool‐aged and school‐aged children infected with Schistosoma mansoni: a randomised controlled, parallel‐group, dose‐ranging, phase 2 trial. Lancet Glob. Health. 5, e688–e698 (2017).
    1. Betson, M. , Sousa‐Figueiredo, J.C. , Rowell, C. , Kabatereine, N.B. & Stothard, J.R. Intestinal schistosomiasis in mothers and young children in Uganda: investigation of field‐applicable markers of bowel morbidity. Am. J. Trop. Med. Hyg. 83, 1048–1055 (2010).
    1. Garba, A. et al Schistosomiasis in infants and preschool‐aged children: infection in a single Schistosoma haematobium and a mixed S. haematobium S. mansoni foci of Niger. Acta Trop. 115, 212–219 (2010).
    1. European Medicines Agency . ICH E11(R1) step 5 guideline on clinical investigation of medicinal products in the pediatric population. EMA/CPMP/ICH/2711/1999. (EMA, London, 2017) <>.
    1. Jung, H. , Medina, R. , Castro, N. , Corona, T. & Sotelo, J. Pharmacokinetic study of praziquantel administered alone and in combination with cimetidine in a single day therapeutic regimen. Antimicrob. Agents Chemother. 41, 1256–1259 (1997).
    1. Westhoff, F. & Blaschke, G. High‐performance liquid chromatographic determination of the stereoselective biotransformation of the chiral drug praziquantel. J. Chromatogr. 578, 265–271 (1992).
    1. Zwang, J. & Olliaro, P.L. Clinical efficacy and tolerability of praziquantel for intestinal and urinary schistosomiasis – a meta‐analysis of comparative and non‐comparative clinical trials. PLoS Negl. Trop. Dis. 8, e3286 (2014).
    1. Coulibaly, J.T. , N'Gbesso, Y.K. , Knopp, S. , Keiser, J. , N'Goran, E.K. & Utzinger, J. Efficacy and safety of praziquantel in preschool‐aged children in an area co‐endemic for Schistosoma mansoni and S. haematobium. PLoS Negl. Trop. Dis. 6, e1917 (2012).
    1. Navaratnam, A.M. , Sousa‐Figueiredo, J.C. , Stothard, J.R. , Kabatereine, N.B. , Fenwick, A. & Mutumba‐Nakalembe, M.J. Efficacy of praziquantel syrup versus crushed praziquantel tablets in the treatment of intestinal schistosomiasis in Ugandan preschool children, with observation on compliance and safety. Trans. R. Soc. Trop. Med. Hyg. 106, 400–407 (2012).
    1. Bonate, P.L. et al Extrapolation of praziquantel pharmacokinetics to a pediatric population: a cautionary tale. J. Pharmacokinet. Pharmacodyn. 45, 747–762 (2018).

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa