Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa

W. Robert Taylor, Htee Khu Naw, Kathryn Maitland, Thomas N. Williams, Melissa Kapulu, Umberto D'Alessandro, James A. Berkley, Philip Bejon, Joseph Okebe, Jane Achan, Alfred Ngwa Amambua, Muna Affara, Davis Nwakanma, Jean Pierre van Geertruyden, Muhindo Mavoko, Pascal Lutumba, Junior Matangila, Philipe Brasseur, Patrice Piola, Rindra RandremananaEstrella Lasry, Caterina Fanello, Marie Onyamboko, Birgit Schramm, Zolia Yah, Joel Jones, Rick M. Fairhurst, Mahamadou Diakite, Grace Malenga, Malcolm Molyneux, Claude Rwagacondo, Charles Obonyo, Endalamaw Gadisa, Abraham Aseffa, Mores Loolpapit, Marie Claire Henry, Grant Dorsey, Chandy John, Sodiomon B. Sirima, Karen I. Barnes, Peter Kremsner, Nicholas P. Day, Nicholas J. White, Mavuto Mukaka

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Methods: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results: From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. Conclusions: We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.

Original languageEnglish (US)
Article number11
JournalBMC Medicine
Volume16
Issue number1
DOIs
StatePublished - Jan 18 2018

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Primaquine
Falciparum Malaria
Africa South of the Sahara
Anemia
Glucosephosphate Dehydrogenase Deficiency
Hemolytic Anemia
Malaria
Plasmodium falciparum
Epidemiology
Therapeutics
Randomized Controlled Trials

Keywords

  • Age-based dosing
  • Malaria
  • Plasmodium falciparum
  • Primaquine
  • Transmission blocking

ASJC Scopus subject areas

  • Medicine(all)

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Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa. / Taylor, W. Robert; Naw, Htee Khu; Maitland, Kathryn; Williams, Thomas N.; Kapulu, Melissa; D'Alessandro, Umberto; Berkley, James A.; Bejon, Philip; Okebe, Joseph; Achan, Jane; Amambua, Alfred Ngwa; Affara, Muna; Nwakanma, Davis; van Geertruyden, Jean Pierre; Mavoko, Muhindo; Lutumba, Pascal; Matangila, Junior; Brasseur, Philipe; Piola, Patrice; Randremanana, Rindra; Lasry, Estrella; Fanello, Caterina; Onyamboko, Marie; Schramm, Birgit; Yah, Zolia; Jones, Joel; Fairhurst, Rick M.; Diakite, Mahamadou; Malenga, Grace; Molyneux, Malcolm; Rwagacondo, Claude; Obonyo, Charles; Gadisa, Endalamaw; Aseffa, Abraham; Loolpapit, Mores; Henry, Marie Claire; Dorsey, Grant; John, Chandy; Sirima, Sodiomon B.; Barnes, Karen I.; Kremsner, Peter; Day, Nicholas P.; White, Nicholas J.; Mukaka, Mavuto.

In: BMC Medicine, Vol. 16, No. 1, 11, 18.01.2018.

Research output: Contribution to journalArticle

Taylor, WR, Naw, HK, Maitland, K, Williams, TN, Kapulu, M, D'Alessandro, U, Berkley, JA, Bejon, P, Okebe, J, Achan, J, Amambua, AN, Affara, M, Nwakanma, D, van Geertruyden, JP, Mavoko, M, Lutumba, P, Matangila, J, Brasseur, P, Piola, P, Randremanana, R, Lasry, E, Fanello, C, Onyamboko, M, Schramm, B, Yah, Z, Jones, J, Fairhurst, RM, Diakite, M, Malenga, G, Molyneux, M, Rwagacondo, C, Obonyo, C, Gadisa, E, Aseffa, A, Loolpapit, M, Henry, MC, Dorsey, G, John, C, Sirima, SB, Barnes, KI, Kremsner, P, Day, NP, White, NJ & Mukaka, M 2018, 'Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa', BMC Medicine, vol. 16, no. 1, 11. https://doi.org/10.1186/s12916-017-0990-6
Taylor, W. Robert ; Naw, Htee Khu ; Maitland, Kathryn ; Williams, Thomas N. ; Kapulu, Melissa ; D'Alessandro, Umberto ; Berkley, James A. ; Bejon, Philip ; Okebe, Joseph ; Achan, Jane ; Amambua, Alfred Ngwa ; Affara, Muna ; Nwakanma, Davis ; van Geertruyden, Jean Pierre ; Mavoko, Muhindo ; Lutumba, Pascal ; Matangila, Junior ; Brasseur, Philipe ; Piola, Patrice ; Randremanana, Rindra ; Lasry, Estrella ; Fanello, Caterina ; Onyamboko, Marie ; Schramm, Birgit ; Yah, Zolia ; Jones, Joel ; Fairhurst, Rick M. ; Diakite, Mahamadou ; Malenga, Grace ; Molyneux, Malcolm ; Rwagacondo, Claude ; Obonyo, Charles ; Gadisa, Endalamaw ; Aseffa, Abraham ; Loolpapit, Mores ; Henry, Marie Claire ; Dorsey, Grant ; John, Chandy ; Sirima, Sodiomon B. ; Barnes, Karen I. ; Kremsner, Peter ; Day, Nicholas P. ; White, Nicholas J. ; Mukaka, Mavuto. / Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa. In: BMC Medicine. 2018 ; Vol. 16, No. 1.
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title = "Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa",
abstract = "Background: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Methods: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results: From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03{\%}), (ii) 1-5 years (n = 261,036, 45.46{\%}), (iii) 6-9 years (n = 20,770, 3.14{\%}), (iv) 10-14 years (n = 12,155, 1.84{\%}) and (v) ≥15 years (n = 328,132, 49.57{\%}) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8{\%} (327,620/328,132), respectively. Conclusions: We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.",
keywords = "Age-based dosing, Malaria, Plasmodium falciparum, Primaquine, Transmission blocking",
author = "Taylor, {W. Robert} and Naw, {Htee Khu} and Kathryn Maitland and Williams, {Thomas N.} and Melissa Kapulu and Umberto D'Alessandro and Berkley, {James A.} and Philip Bejon and Joseph Okebe and Jane Achan and Amambua, {Alfred Ngwa} and Muna Affara and Davis Nwakanma and {van Geertruyden}, {Jean Pierre} and Muhindo Mavoko and Pascal Lutumba and Junior Matangila and Philipe Brasseur and Patrice Piola and Rindra Randremanana and Estrella Lasry and Caterina Fanello and Marie Onyamboko and Birgit Schramm and Zolia Yah and Joel Jones and Fairhurst, {Rick M.} and Mahamadou Diakite and Grace Malenga and Malcolm Molyneux and Claude Rwagacondo and Charles Obonyo and Endalamaw Gadisa and Abraham Aseffa and Mores Loolpapit and Henry, {Marie Claire} and Grant Dorsey and Chandy John and Sirima, {Sodiomon B.} and Barnes, {Karen I.} and Peter Kremsner and Day, {Nicholas P.} and White, {Nicholas J.} and Mavuto Mukaka",
year = "2018",
month = "1",
day = "18",
doi = "10.1186/s12916-017-0990-6",
language = "English (US)",
volume = "16",
journal = "BMC Medicine",
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TY - JOUR

T1 - Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa

AU - Taylor, W. Robert

AU - Naw, Htee Khu

AU - Maitland, Kathryn

AU - Williams, Thomas N.

AU - Kapulu, Melissa

AU - D'Alessandro, Umberto

AU - Berkley, James A.

AU - Bejon, Philip

AU - Okebe, Joseph

AU - Achan, Jane

AU - Amambua, Alfred Ngwa

AU - Affara, Muna

AU - Nwakanma, Davis

AU - van Geertruyden, Jean Pierre

AU - Mavoko, Muhindo

AU - Lutumba, Pascal

AU - Matangila, Junior

AU - Brasseur, Philipe

AU - Piola, Patrice

AU - Randremanana, Rindra

AU - Lasry, Estrella

AU - Fanello, Caterina

AU - Onyamboko, Marie

AU - Schramm, Birgit

AU - Yah, Zolia

AU - Jones, Joel

AU - Fairhurst, Rick M.

AU - Diakite, Mahamadou

AU - Malenga, Grace

AU - Molyneux, Malcolm

AU - Rwagacondo, Claude

AU - Obonyo, Charles

AU - Gadisa, Endalamaw

AU - Aseffa, Abraham

AU - Loolpapit, Mores

AU - Henry, Marie Claire

AU - Dorsey, Grant

AU - John, Chandy

AU - Sirima, Sodiomon B.

AU - Barnes, Karen I.

AU - Kremsner, Peter

AU - Day, Nicholas P.

AU - White, Nicholas J.

AU - Mukaka, Mavuto

PY - 2018/1/18

Y1 - 2018/1/18

N2 - Background: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Methods: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results: From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. Conclusions: We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.

AB - Background: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Methods: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results: From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. Conclusions: We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.

KW - Age-based dosing

KW - Malaria

KW - Plasmodium falciparum

KW - Primaquine

KW - Transmission blocking

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DO - 10.1186/s12916-017-0990-6

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VL - 16

JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

IS - 1

M1 - 11

ER -