Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments
The antischistosomal drug oxamniquine, OXA, requires activation by a sulfotransferase within the parasitic worm to enable killing. Examination of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for OXA identified an in vitro-in vivo paradox with the maximal clinical plasma concentrations fi...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320723000039 |
| _version_ | 1797855275504369664 |
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| author | Katalin Toth Sevan Alwan Susan Khan Stanton F. McHardy Philip T. LoVerde Michael D. Cameron |
| author_facet | Katalin Toth Sevan Alwan Susan Khan Stanton F. McHardy Philip T. LoVerde Michael D. Cameron |
| author_sort | Katalin Toth |
| collection | DOAJ |
| description | The antischistosomal drug oxamniquine, OXA, requires activation by a sulfotransferase within the parasitic worm to enable killing. Examination of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for OXA identified an in vitro-in vivo paradox with the maximal clinical plasma concentrations five-to ten-times lower than the efficacious concentration for in vitro schistosomal killing. The parasite resides in the vasculature between the intestine and the liver, and modeling the PK data to determine portal concentrations fits with in vitro studies and explains the required human dose. In silico models were used to predict murine dosing to recapitulate human conditions for OXA portal concentration and time course. Follow-up PK studies verified in mice that a 50–100 mg/kg oral gavage dose of OXA formulated in acetate buffer recapitulates the 20–40 mg/kg dose common in patients. OXA was rapidly cleared through a combination of metabolism and excretion into bile. OXA absorbance and tissue distribution were similar in wild-type and P-gp efflux transporter knockout mice. The incorporation of in vitro efficacy data and portal concentration was demonstrated for an improved OXA-inspired analog that has been shown to kill S. mansoni, S. haematobium, and S. japonicum, whereas OXA is only effective against S. mansoni. Second-generation OXA analogs should optimize both in vitro killing and physiochemical properties to achieve high portal concentration via rapid oral absorption, facilitated by favorable solubility, permeability, and minimal intestinal metabolism. |
| first_indexed | 2024-04-09T20:21:06Z |
| format | Article |
| id | doaj.art-999c478cae974c1bb2e1a32eba6f33a5 |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-04-09T20:21:06Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-999c478cae974c1bb2e1a32eba6f33a52023-03-31T05:53:19ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072023-04-01216573Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatmentsKatalin Toth0Sevan Alwan1Susan Khan2Stanton F. McHardy3Philip T. LoVerde4Michael D. Cameron5Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL, 33458, United StatesDepartment of Biochemistry and Structural Biology, UT Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, United StatesDepartment of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL, 33458, United StatesCenter for Innovative Drug Discovery, University of Texas at San Antonio, Department of Chemistry, One UTSA Circle, San Antonio, TX, 78249, United StatesDepartment of Biochemistry and Structural Biology, UT Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, United StatesDepartment of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL, 33458, United States; Corresponding author.The antischistosomal drug oxamniquine, OXA, requires activation by a sulfotransferase within the parasitic worm to enable killing. Examination of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for OXA identified an in vitro-in vivo paradox with the maximal clinical plasma concentrations five-to ten-times lower than the efficacious concentration for in vitro schistosomal killing. The parasite resides in the vasculature between the intestine and the liver, and modeling the PK data to determine portal concentrations fits with in vitro studies and explains the required human dose. In silico models were used to predict murine dosing to recapitulate human conditions for OXA portal concentration and time course. Follow-up PK studies verified in mice that a 50–100 mg/kg oral gavage dose of OXA formulated in acetate buffer recapitulates the 20–40 mg/kg dose common in patients. OXA was rapidly cleared through a combination of metabolism and excretion into bile. OXA absorbance and tissue distribution were similar in wild-type and P-gp efflux transporter knockout mice. The incorporation of in vitro efficacy data and portal concentration was demonstrated for an improved OXA-inspired analog that has been shown to kill S. mansoni, S. haematobium, and S. japonicum, whereas OXA is only effective against S. mansoni. Second-generation OXA analogs should optimize both in vitro killing and physiochemical properties to achieve high portal concentration via rapid oral absorption, facilitated by favorable solubility, permeability, and minimal intestinal metabolism.http://www.sciencedirect.com/science/article/pii/S2211320723000039OxamniquineSchistosomeSchistosomiasisParasitic wormPK/PD relationship |
| spellingShingle | Katalin Toth Sevan Alwan Susan Khan Stanton F. McHardy Philip T. LoVerde Michael D. Cameron Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments International Journal for Parasitology: Drugs and Drug Resistance Oxamniquine Schistosome Schistosomiasis Parasitic worm PK/PD relationship |
| title | Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments |
| title_full | Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments |
| title_fullStr | Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments |
| title_full_unstemmed | Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments |
| title_short | Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments |
| title_sort | addressing the oxamniquine in vitro in vivo paradox to facilitate a new generation of anti schistosome treatments |
| topic | Oxamniquine Schistosome Schistosomiasis Parasitic worm PK/PD relationship |
| url | http://www.sciencedirect.com/science/article/pii/S2211320723000039 |
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