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Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis

  • STEPHEN WRING (a1), ERIC GAUKEL (a1), BAKELA NARE (a1), ROBERT JACOBS (a1), BETH BEAUDET (a1), TANA BOWLING (a1), LUKE MERCER (a1), CYRUS BACCHI (a2), NIGEL YARLETT (a2), RYAN RANDOLPH (a1), ROBIN PARHAM (a1), CINDY REWERTS (a1), JACOB PLATNER (a3) and ROBERT DON (a4)...

Summary

This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic–pharmacodynamic (PK–PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic–pharmacodyamic studies in animal infection models.

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      Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis
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Copyright

The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution license .

Corresponding author

*Corresponding author: SCYNEXIS Inc., Research Triangle Park, North Carolina, USA. Tel: +(919) 544 8600. Fax: +(919) 544 8697. E-mail: stevewring@mac.com

References

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Allen, T. H., Krzywicki, H. J. and Roberts, E. (1959). Density, fat, water and solids in freshly isolated tissues. Journal of Applied Physiology 14, 10051008.
Annesely, T. M. (2003). Ion suppression in mass spectrometry. Clinical Chemistry 49, 10411044.
Burri, C. and Keiser, J. (2001). Pharmacokinetic investigations in patients from Northern Angola refractory to Melarsoprol treatment. Tropical Medicine International Health 6, 412420.
Burri, C., Onyango, J. D., Auma, J. E., Burudi, E. M. E. and Brun, R. (1994). Pharmacokinetics of Melarsoprol in uninfected Vervet monkeys. Acta Tropica 58, 3549.
Delespaux, V. and de Koning, H. P. (2007). Drugs and drug resistance in African Trypanosomiasis. Drug Resistance Updates 10, 3050.
Doua, F., Asumu, P. N., Cimarro, P. P. and Burri, C. (2005). Effectiveness of a 10-day Melarsoprol schedule for the treatment of late-stage Human African Trypanosomiasis: confirmation from a multinational study (IMPAMEL II). Journal of Infectious Diseases 191, 19221931.
Fridén, M., Gupta, A., Antonsson, M., Bredberg, U. and Hammarlund-Udenaes, M. (2007). In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metabolism and Disposition 35, 17111719.
Fridén, M., Ljungqvist, H., Middleton, B., Bredberg, U. and Hammarlund-Udenaes, M. (2009). Improved measurement of drug exposure in the brain using drug-specific correction for residual blood. Journal Cerebral Blood Flow and Metabolism 30, 150161.
Friedman, J. J. (1959). Circulating and tissue hematocrits of normal ananesthetized mic. American Journal of Physiology 196, 420422.
Grab, D. J., Nikolskaia, O., Kim, Y. V., Lonsdale-Eccles, J. D., Ito, S., Hara, T., Fukuma, T., Nyarko, E., Kim, K. J., Stins, M. F., Delannoy, M. J., Rodgers, J. and Kim, K. S. (2004). African Trypanosome interactions with an in vitro model of the human blood-brain barrier. Journal of Parasitology 90, 970979.
Jacobs, R. T., Nare, B., Wring, S. A., Orr, M. D., Chen, D., Sligar, J. M., Jenks, M. X., Noe, R. A., Bowling, T. S., Mercer, L. T., Rewerts, C., Gaukel, E., Owens, J., Parham, R., Randolph, R., Beaudet, B., Bacchi, C. J., Yarlett, N., Plattner, J. J., Freund, Y., Ding, C., Akama, T., Zhang, Y.-K., Brun, R., Kaiser, M., Scandale, I. and Don, R. (2011). SCYX-7158, an orally-active benzoxaborole for the treatment of stage 2 human African trypanosomiasis. PLoS Neglected Tropical Diseases 5, 111.
Jennings, F. and Gray, G. (1983). Relapsed parasitemia following chemotherapy of chronic T. brucei infections in mice and its relation to cerebral trypanosomes. Contributions to Microbiology and Immunology 7, 147154.
Kuepfer, I., Schmid, C., Allan, M., Edielu, A., Haary, E., Kakembo, A., Kibona, S., Blum, J. and Burri, C. (2012). Safety and efficacy of the 10-Day Melarsoprol schedule for the treatment of second stage rhodesiense sleeping sickness. PLoS Neglected Tropical Diseases 6, e1695.
Legros, D., Evans, S., Maiso, F., Enyaru, J. C. K. and Mbulamberi, D. (1999). Risk factors for treatment failure after Melarsoprol for Trypanosoma brucei gambiense trypanosomiasis in Uganda. Transactions of the Royal Society of Tropical Medical Hygiene 93, 439442.
Likefack, A. C. L., Brun, R., Fomena, A. and Truc, P. (2006). Comparison of the in vitro drug sensitivity of Trypanosoma brucei gambiense strains from west and central Africa isolated in the periods 1960–1995 and 1999–2004. Acta Tropica 100, 1116.
Lin, J. H. (2008). CSF as a surrogate for assessing CNS exposure: an industrial perspective. Current Drug Metabolism 9, 4659.
Louie, A., Deziel, M., Liu, W., Drusano, M. F., Gumbo, T. and Drusano, G. L. (2005). Pharmacodynamics of Caspofungin in a murine model of systemic Candidiasis: importance of persistence of Caspofungin in tissues to understanding drug activity. Antimicrobial Agents and Chemotherapy 49, 50585068.
MacKichan, J. J. (2005). Influence of protein binding and use of unbound (free) drug concentrations. In: Applied Pharmacokinetics and Pharmacodynamics: Principles of Therapeutic Drug Monitoring, 4th Edn (ed. Burton, M. E., Shaw, L. M., Schentag, J. J. and Evans, W. E.), pp. 82120. Lippincott Williams & Wilkins, Philadelphia, USA.
Mahar Doan, K. M., Wring, S. A., Shampine, L. J., Jordan, K. H., Bishop, J. P., Kratz, J., Yang, E., Serabjit-Singh, C. J., Adkison, K. K. and Polli, J. W. (2004). Steady-state brain concentrations of antihistamines in rats. Pharmacology 72, 9298.
Mandagere, A. K., Thompson, T. N. and Hwang, K. (2002). Graphical model for estimating oral bioavailability of drugs in humans and other species from their Caco-2 permeability and in vitro liver enzyme metabolic stability rates. Journal of Medicinal Chemistry 45, 304311.
Masocha, W., Rottenberg, M. E. and Kristensson, K. (2007). Migration of African trypanosomes across the blood-brain barrier. Physiology and Behavior 92, 110114.
Matovu, E., Enyaru, J. C. K., Legros, D., Schmid, C., Seebeck, T. and Kaminsky, R. (2001). Melarsoprol refractory T. b. gambiense from Omugo, North-Western Uganda. Tropical Medicine and International Health 6, 407411.
Milford, F., Loko, L., Ethier, L., Mpia, B. and Pepin, J. (1993). Eflorinithine concentrations in serum and cerebrospinal fluid of 63 patients treated for Trypanosoma brucei gambiense sleeping sickness. Transactions of the Royal Society for Tropical Medicine and Hygiene 87, 473477.
Mueller, M., de la Pena, A. and Derendorf, H. (2004). Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: kill curves versus MIC. Antimicrobial Agents and Chemotherapy 48, 369377.
Nare, B., Wring, S., Bacchi, C., Beaudet, B., Bowling, T., Brun, R., Chen, D., Ding, C., Freund, Y., Gaukel, E., Hussain, A., Jarnagin, K., Jenks, M., Kaiser, M., Mercer, L., Mejia, E., Noe, A., Orr, M., Parham, R., Plattner, J., Randolph, R., Rattendi, D., Rewerts, C., Sligar, J., Yarlett, N., Don, R. and Jacobs, R. (2010). Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system African trypanosomiasis. Antimicrobial Agents and Chemotherapy 54, 43794388.
Polli, J. W., Wring, S. A., Humphreys, J. E., Huang, L., Morgan, J. B., Webster, L. O. and Serabjit-Singh, C. S. (2001). Rational use of in vitro P-glycoprotein assays in drug discovery. Journal of Pharmacology and Experimental Therapeutics 299, 620628.
Priotto, G., Kasparian, S., Ngouama, D., Ghorashien, S., Arnold, U., Ghabri, S. and Karunakara, (2007). Nifurtomox-eflornithine combination therapy for second-stage Trypanosoma brucei gambiense sleeping slickness: a randomized trial in Congo. CSE Theme Article, CID 45, 14351442.
Priotto, G., Pinoges, L., Fursa, I. B., Burke, B., Nicolay, N., Grillet, G., Hewison, C. and Balasegaram, M. (2008). Safety and effectiveness of first line Eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study. British Medical Journal 336, 705708.
Sanderson, L., Dogruel, M., Rodgers, J., Bradley, B. and Thomas, S. A. (2008). The blood-brain barrier significantly limits eflornithine entry into the Trypanosoma brucei brucei infected Mouse Brain. Journal of Neurochemistry 107, 1136.
Sanderson, L., Dogruel, M., Rodgers, J., De Koning, H. P. and Thomas, S. A. (2009). Pentamidine movement across the murine blood-brain and blood-cerebrospinal fluid barriers: effect of trypanosome infection, combination therapy, P-glycoprotein, and multidrug resistance-associated protein. Journal of Pharmacology and Experimental Therapeutics 329, 967977.
Schmid, C., Nkunku, S., Merolle, A., Vounatsou, P. and Burri, C. (2004). Efficacy of 10-day Melarsoprol schedule 2 years after treatment for late-stage gambiense sleeping sickness. Lancet 364, 789790.
Shen, D. D., Artru, A. A. and Adkinson, K. K. (2004). Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. Advanced Drug Delivery Reviews 56, 18251857.
Summerfield, S. G. and Jeffrey, P. (2006). In vitro prediction of brain penetration – a case for free thinking. Expert Opinion 1, 595607.
Summerfield, S. G., Stevens, A. J., Cutler, L., del Carmen Osuna, M., Hammond, B., Tang, S., Hersey, A., Spalding, D. J. and Jeffrey, P. (2006). Improving the in vitro prediction of in vivo central nervous system penetration: integrating permeability, P-glycoprotein efflux, and free fractions in blood and brain. Drug Metabolism and Disposition 316, 12821290.
Thiel-Demby, V. E., Tippin, T. K., Humphreys, J. E., Serabjit-Singh, C. J. and Polli, J. W. (2004). In vitro absorption and secretory quotients: practical criteria derived from a study of 331 compounds to assess for the impact of P-glycoprotein-mediated efflux on drug candidates. Journal Pharmaceutical Science 93, 25672572.
Torreele, E., Bourdin Trunz, B., Tweats, D., Kaiser, M., Brun, R., Mazué, G., Bray, M. and Pécoul, B. (2010). Fexinidazole – a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Neglected Tropical Diseases 4, e923.
Troutman, M. D. and Thakker, D. R. (2003). Novel experimental parameters to quantify the modulation of absorptive and secretory transport of compounds by P- glycoprotein in cell culture models of intestinal epithelium. Pharmaceutical Research 20, 12101224.
Vérant, P., Serduc, R., Van Der Sanden, B., Rémy, C. and Vial, J.-C. (2007). A direct method for measuring mouse capillary cortical blood volume using multiphoton laser scanning microscopy. Journal of Cerebral Blood Flow and Metabolism 27, 10721081.
Watson, J., Wright, S., Lucas, A., Clarke, K. L., Viggers, J., Cheetham, S., Jeffrey, P., Porter, R. and Read, K. D. (2009). Receptor occupancy and brain free fraction. Drug Metabolism and Disposition 37, 753760.
WHO (2006). Weekly Epidemiological Record 81, 6980.
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Parasitology
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