Optimal antimalarial dose regimens for sulfadoxine-pyrimethamine with and without azithromycin in pregnancy based on population pharmacokinetic modeling

Sam Salman, Francisca Baiwog, Madhu Page-Sharp, Susan Griffin, Harin Ashley Karunajeewa, Ivo Mueller, Stephen J Rogerson, Peter Siba, Kenneth Ilett, Timothy Davis

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Abstract

Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when co-administered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 non-pregnant and 45 pregnant women treated with SP-AZI (n=15 in each group) and SP-chloroquine (n=30 in each group) were analyzed. Population non-linear mixed effects pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX) and N-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX and NASDOX by 48%, 29% and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46%, 99%) and NASDOX (46%). Co-administration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design including the use of an early postpartum follow-up study rather than a non-pregnant comparator group. Simulations based on the final population model demonstrated that, compared with conventional single-dose SP in non-pregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials employing recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings, and consideration given to using increased doses in future trials.
Original languageEnglish
Article numbere02291
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number5
DOIs
Publication statusPublished - May 2017

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Azithromycin
Antimalarials
Pharmacokinetics
Pregnancy
Population
Pregnant Women
Pyrimethamine
pyrimethamine drug combination fanasil
Sulfadoxine
Chloroquine
Postpartum Period

Cite this

Salman, Sam ; Baiwog, Francisca ; Page-Sharp, Madhu ; Griffin, Susan ; Karunajeewa, Harin Ashley ; Mueller, Ivo ; Rogerson, Stephen J ; Siba, Peter ; Ilett, Kenneth ; Davis, Timothy. / Optimal antimalarial dose regimens for sulfadoxine-pyrimethamine with and without azithromycin in pregnancy based on population pharmacokinetic modeling. In: Antimicrobial Agents and Chemotherapy. 2017 ; Vol. 61, No. 5.
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abstract = "Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when co-administered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 non-pregnant and 45 pregnant women treated with SP-AZI (n=15 in each group) and SP-chloroquine (n=30 in each group) were analyzed. Population non-linear mixed effects pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX) and N-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX and NASDOX by 48{\%}, 29{\%} and 70{\%}, respectively, as well as the relative volumes of distribution (V/F) of PYR (46{\%}, 99{\%}) and NASDOX (46{\%}). Co-administration of AZI resulted in a greater increase in PYR CL/F (80{\%}) and also increased NASDOX V/F by 76{\%}. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design including the use of an early postpartum follow-up study rather than a non-pregnant comparator group. Simulations based on the final population model demonstrated that, compared with conventional single-dose SP in non-pregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials employing recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings, and consideration given to using increased doses in future trials.",
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Optimal antimalarial dose regimens for sulfadoxine-pyrimethamine with and without azithromycin in pregnancy based on population pharmacokinetic modeling. / Salman, Sam; Baiwog, Francisca; Page-Sharp, Madhu; Griffin, Susan; Karunajeewa, Harin Ashley; Mueller, Ivo; Rogerson, Stephen J; Siba, Peter; Ilett, Kenneth; Davis, Timothy.

In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 5, e02291, 05.2017.

Research output: Contribution to journalArticle

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AU - Salman, Sam

AU - Baiwog, Francisca

AU - Page-Sharp, Madhu

AU - Griffin, Susan

AU - Karunajeewa, Harin Ashley

AU - Mueller, Ivo

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AU - Siba, Peter

AU - Ilett, Kenneth

AU - Davis, Timothy

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N2 - Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when co-administered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 non-pregnant and 45 pregnant women treated with SP-AZI (n=15 in each group) and SP-chloroquine (n=30 in each group) were analyzed. Population non-linear mixed effects pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX) and N-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX and NASDOX by 48%, 29% and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46%, 99%) and NASDOX (46%). Co-administration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design including the use of an early postpartum follow-up study rather than a non-pregnant comparator group. Simulations based on the final population model demonstrated that, compared with conventional single-dose SP in non-pregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials employing recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings, and consideration given to using increased doses in future trials.

AB - Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when co-administered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 non-pregnant and 45 pregnant women treated with SP-AZI (n=15 in each group) and SP-chloroquine (n=30 in each group) were analyzed. Population non-linear mixed effects pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX) and N-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX and NASDOX by 48%, 29% and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46%, 99%) and NASDOX (46%). Co-administration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design including the use of an early postpartum follow-up study rather than a non-pregnant comparator group. Simulations based on the final population model demonstrated that, compared with conventional single-dose SP in non-pregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials employing recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings, and consideration given to using increased doses in future trials.

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DO - 10.1128/AAC.02291-16

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SN - 0066-4804

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