Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling

Sam Salman, Francesca Baiwog, Madhu Page-Sharp, Kay Kose, Harin A. Karunajeewa, Ivo Mueller, Stephen J. Rogerson, Peter M. Siba, Kenneth F. Ilett, Timothy M.E. Davis

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    Despite extensive use and accumulated evidence of safety, there have been few pharmacokinetic studies from which appropriate chloroquine (CQ) dosing regimens could be developed specifically for pregnant women. Such optimised CQ-based regimens, used as treatment for acute malaria or as intermittent preventive treatment in pregnancy (IPTp), may have a valuable role if parasite CQ sensitivity returns following reduced drug pressure. In this study, population pharmacokinetic/pharmacodynamic modelling was used to simultaneously analyse plasma concentration-time data for CQ and its active metabolite desethylchloroquine (DCQ) in 44 non-pregnant and 45 pregnant Papua New Guinean women treated with CQ and sulfadoxine/pyrimethamine or azithromycin (AZM). Pregnancy was associated with 16% and 49% increases in CQ and DCQ clearance, respectively, as well as a 24% reduction in CQ relative bioavailability. Clearance of DCQ was 22% lower in those who received AZM in both groups. Simulations based on the final multicompartmental model demonstrated that a 33% CQ dose increase may be suitable for acute treatment for malaria in pregnancy as it resulted in equivalent exposure to that in non-pregnant women receiving recommended doses, whilst a double dose would likely be required for an effective duration of post-treatment prophylaxis when used as IPTp especially in areas of CQ resistance. The impact of co-administered AZM was clinically insignificant in simulations. The results of past/ongoing trials employing recommended adult doses of CQ-based regimens in pregnant women should be interpreted in light of these findings, and consideration should be given to using increased doses in future trials.

    Original languageEnglish
    Pages (from-to)542–551
    JournalInternational Journal of Antimicrobial Agents
    Volume50
    Issue number4
    DOIs
    Publication statusPublished - Oct 2017

    Fingerprint

    Chloroquine
    Antimalarials
    Pharmacokinetics
    Pregnancy
    Population
    Azithromycin
    Pregnant Women
    Therapeutics
    Biological Availability
    Parasites
    Safety
    Pressure

    Cite this

    Salman, Sam ; Baiwog, Francesca ; Page-Sharp, Madhu ; Kose, Kay ; Karunajeewa, Harin A. ; Mueller, Ivo ; Rogerson, Stephen J. ; Siba, Peter M. ; Ilett, Kenneth F. ; Davis, Timothy M.E. / Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling. In: International Journal of Antimicrobial Agents. 2017 ; Vol. 50, No. 4. pp. 542–551.
    @article{ff91c1f63f7746428477a48518da61bb,
    title = "Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling",
    abstract = "Despite extensive use and accumulated evidence of safety, there have been few pharmacokinetic studies from which appropriate chloroquine (CQ) dosing regimens could be developed specifically for pregnant women. Such optimised CQ-based regimens, used as treatment for acute malaria or as intermittent preventive treatment in pregnancy (IPTp), may have a valuable role if parasite CQ sensitivity returns following reduced drug pressure. In this study, population pharmacokinetic/pharmacodynamic modelling was used to simultaneously analyse plasma concentration-time data for CQ and its active metabolite desethylchloroquine (DCQ) in 44 non-pregnant and 45 pregnant Papua New Guinean women treated with CQ and sulfadoxine/pyrimethamine or azithromycin (AZM). Pregnancy was associated with 16{\%} and 49{\%} increases in CQ and DCQ clearance, respectively, as well as a 24{\%} reduction in CQ relative bioavailability. Clearance of DCQ was 22{\%} lower in those who received AZM in both groups. Simulations based on the final multicompartmental model demonstrated that a 33{\%} CQ dose increase may be suitable for acute treatment for malaria in pregnancy as it resulted in equivalent exposure to that in non-pregnant women receiving recommended doses, whilst a double dose would likely be required for an effective duration of post-treatment prophylaxis when used as IPTp especially in areas of CQ resistance. The impact of co-administered AZM was clinically insignificant in simulations. The results of past/ongoing trials employing recommended adult doses of CQ-based regimens in pregnant women should be interpreted in light of these findings, and consideration should be given to using increased doses in future trials.",
    keywords = "Chloroquine, Malaria, Pharmacokinetics, Pregnancy",
    author = "Sam Salman and Francesca Baiwog and Madhu Page-Sharp and Kay Kose and Karunajeewa, {Harin A.} and Ivo Mueller and Rogerson, {Stephen J.} and Siba, {Peter M.} and Ilett, {Kenneth F.} and Davis, {Timothy M.E.}",
    year = "2017",
    month = "10",
    doi = "10.1016/j.ijantimicag.2017.05.011",
    language = "English",
    volume = "50",
    pages = "542–551",
    journal = "International Journal of Antimicrobial Agents",
    issn = "0924-8579",
    publisher = "Pergamon",
    number = "4",

    }

    Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling. / Salman, Sam; Baiwog, Francesca; Page-Sharp, Madhu; Kose, Kay; Karunajeewa, Harin A.; Mueller, Ivo; Rogerson, Stephen J.; Siba, Peter M.; Ilett, Kenneth F.; Davis, Timothy M.E.

    In: International Journal of Antimicrobial Agents, Vol. 50, No. 4, 10.2017, p. 542–551.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling

    AU - Salman, Sam

    AU - Baiwog, Francesca

    AU - Page-Sharp, Madhu

    AU - Kose, Kay

    AU - Karunajeewa, Harin A.

    AU - Mueller, Ivo

    AU - Rogerson, Stephen J.

    AU - Siba, Peter M.

    AU - Ilett, Kenneth F.

    AU - Davis, Timothy M.E.

    PY - 2017/10

    Y1 - 2017/10

    N2 - Despite extensive use and accumulated evidence of safety, there have been few pharmacokinetic studies from which appropriate chloroquine (CQ) dosing regimens could be developed specifically for pregnant women. Such optimised CQ-based regimens, used as treatment for acute malaria or as intermittent preventive treatment in pregnancy (IPTp), may have a valuable role if parasite CQ sensitivity returns following reduced drug pressure. In this study, population pharmacokinetic/pharmacodynamic modelling was used to simultaneously analyse plasma concentration-time data for CQ and its active metabolite desethylchloroquine (DCQ) in 44 non-pregnant and 45 pregnant Papua New Guinean women treated with CQ and sulfadoxine/pyrimethamine or azithromycin (AZM). Pregnancy was associated with 16% and 49% increases in CQ and DCQ clearance, respectively, as well as a 24% reduction in CQ relative bioavailability. Clearance of DCQ was 22% lower in those who received AZM in both groups. Simulations based on the final multicompartmental model demonstrated that a 33% CQ dose increase may be suitable for acute treatment for malaria in pregnancy as it resulted in equivalent exposure to that in non-pregnant women receiving recommended doses, whilst a double dose would likely be required for an effective duration of post-treatment prophylaxis when used as IPTp especially in areas of CQ resistance. The impact of co-administered AZM was clinically insignificant in simulations. The results of past/ongoing trials employing recommended adult doses of CQ-based regimens in pregnant women should be interpreted in light of these findings, and consideration should be given to using increased doses in future trials.

    AB - Despite extensive use and accumulated evidence of safety, there have been few pharmacokinetic studies from which appropriate chloroquine (CQ) dosing regimens could be developed specifically for pregnant women. Such optimised CQ-based regimens, used as treatment for acute malaria or as intermittent preventive treatment in pregnancy (IPTp), may have a valuable role if parasite CQ sensitivity returns following reduced drug pressure. In this study, population pharmacokinetic/pharmacodynamic modelling was used to simultaneously analyse plasma concentration-time data for CQ and its active metabolite desethylchloroquine (DCQ) in 44 non-pregnant and 45 pregnant Papua New Guinean women treated with CQ and sulfadoxine/pyrimethamine or azithromycin (AZM). Pregnancy was associated with 16% and 49% increases in CQ and DCQ clearance, respectively, as well as a 24% reduction in CQ relative bioavailability. Clearance of DCQ was 22% lower in those who received AZM in both groups. Simulations based on the final multicompartmental model demonstrated that a 33% CQ dose increase may be suitable for acute treatment for malaria in pregnancy as it resulted in equivalent exposure to that in non-pregnant women receiving recommended doses, whilst a double dose would likely be required for an effective duration of post-treatment prophylaxis when used as IPTp especially in areas of CQ resistance. The impact of co-administered AZM was clinically insignificant in simulations. The results of past/ongoing trials employing recommended adult doses of CQ-based regimens in pregnant women should be interpreted in light of these findings, and consideration should be given to using increased doses in future trials.

    KW - Chloroquine

    KW - Malaria

    KW - Pharmacokinetics

    KW - Pregnancy

    UR - http://www.scopus.com/inward/record.url?scp=85028033968&partnerID=8YFLogxK

    U2 - 10.1016/j.ijantimicag.2017.05.011

    DO - 10.1016/j.ijantimicag.2017.05.011

    M3 - Article

    VL - 50

    SP - 542

    EP - 551

    JO - International Journal of Antimicrobial Agents

    JF - International Journal of Antimicrobial Agents

    SN - 0924-8579

    IS - 4

    ER -