Primaquine Pharmacokinetics in Lactating Women and Their Infants

NCT01780753 | Completed Phase 1

• 1 other identifier: SMRU1203
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The weight of malaria falls most heavily on young children and pregnant women but studies of the safety of antimalarials in pregnancy and lactation are few. The only recommended medication used for radical treatment of P.vivax is primaquine. The 2010 WHO malaria guidelines recommend its use in all patients with P.vivax infection in areas of low transmission, in the absence of contraindications. Primaquine is contraindicated in pregnancy. The postpartum period presents a key opportunity to definitively treat women who suffer multiple malaria relapses during pregnancy. The 2010 WHO malaria treatment guidelines allow for primaquine use during lactation but there are no studies to date quantifying primaquine excretion in breast milk and the dose that breastfed infants would be exposed to is unknown. The investigators propose to study the pharmacokinetics of primaquine in maternal and infant plasma and in breast milk during a 14 day radical treatment of P.vivax. Some inferences about the expected behavior of primaquine in lactation can be drawn from its known pharmacologic properties. Primaquine pharmacokinetics have been well characterized in healthy subjects and malaria patients after single and multiple oral dosing. Peak concentrations are reached within 2-3 hours after dosing and the plasma elimination half-life is \~7 hours. It is extensively distributed in the tissue and largely metabolized to inert carboxyprimaquine, the major plasma metabolite, which undergoes further biotransformation to unknown metabolites that are probably more toxic than the parent compound. The identification of other metabolites in humans has been difficult to pursue because the expected aminophenol metabolites are unstable. No pharmacokinetic studies have been done to measure primaquine excretion in breast milk. A few studies have been done of other antimalarials during lactation and have shown low levels of drug in breast milk during treatment.

Conditions

Vivax Malaria

Keywords

Primaquine; Vivax malaria; G6PD

Outcome Measures

Primary Outcomes (1)

• Pharmacokinetic Parameters of Primaquine and Carboxyprimaquine in breast milk. Area Under Curve (AUC)

  Primaquine and carboxyprimaquine pharmacokinetic parameters to day 13 in breast milk of lactating women treated with primaquine for radical treatment of P.vivax.

  13 Days. Time Frame: predose, 0,1,2,3,4,6,8,12,24,72 hours; Day 7, Day 13 post-dose

Secondary Outcomes (5)

• Pharmacokinetics Parameters of Primaquine and Carboxyprimaquine in blood. Area Under Curve (AUC).

  13 Days. Time Frame: predose, 0,1,2,3,4,6,8,12,24,72 hours; Day 7, Day 13 post-dose

• Concentration of Primaquine in saliva and urine. Area Under Curve (AUC).

  13 Days. Time Frame: predose, 0,1,2,3,4,6,8,12,24,72 hours; Day 7, Day 13 post-dose

• Primaquine dosage in infant - the relative infant dose. Area Under Curve (AUC).

  13 Days. Time Frame: predose, 0,1,2,3,4,6,8,12,24,72 hours; Day 7, Day 13 post-dose

• Assessment of adverse events during primaquine administration

  63 days

• Hematocrit levels in mother and child

  63 days

Study Arms (1)

Primaquine

EXPERIMENTAL

Primaquine GPO® (Government Pharmaceutical Organization, Thailand) 0.5 mg/kg will be given once daily for 14 days.

Drug: Primaquine

Interventions

Primaquine DRUG

Primaquine GPO® (Government Pharmaceutical Organization, Thailand) 0.5 mg/kg will be given once daily for 14 days.

Primaquine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Lactating women aged 18 years and older who are breast feeding one infant aged more than 28 days.
• G6PD normal
• History of proven P.vivax malaria that has not been treated with primaquine
• Willingness and ability to comply with the study protocol for the duration of the trial
• Written informed consent provided

You may not qualify if:

• Known hypersensitivity to primaquine, defined as history of erythroderma/other severe cutaneous reaction, angioedema or anaphylaxis
• Glucose-6-phosphate-dehydrogenase (G6PD) deficiency in mother
• Glucose-6-phosphate-dehydrogenase (G6PD) deficiency in infant
• Pregnancy (urine test for HCG to be performed on any woman of child bearing age unless menstruating)
• Blood smear positive for malaria at the time of enrolment
• Presence of intercurrent illness or any condition which in the judgement of the investigator would place the patient at undue risk or interfere with the results of the study
• Hematocrit (HCT) \<25% in the mother or \<33% in the infant
• Use of medications other than antipyretics in the past 7 days or Chloroquine in the past 2 months.
• Use of primaquine since most recent malaria episode.

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (1)

Shoklo Malaria Research Unit

Mae Sot, Changwat Tak, Thailand

Location

Related Publications (2)

• Wattanakul T, Gilder ME, McGready R, Hanpithakpong W, Day NPJ, White NJ, Nosten F, Tarning J, Hoglund RM. Population pharmacokinetic modelling of primaquine exposures in lactating women and breastfed infants. Nat Commun. 2024 May 8;15(1):3851. doi: 10.1038/s41467-024-47908-y.

  PMID: 38719803 DERIVED

• Gilder ME, Hanpithakphong W, Hoglund RM, Tarning J, Win HH, Hilda N, Chu CS, Bancone G, Carrara VI, Singhasivanon P, White NJ, Nosten F, McGready R. Primaquine Pharmacokinetics in Lactating Women and Breastfed Infant Exposures. Clin Infect Dis. 2018 Sep 14;67(7):1000-1007. doi: 10.1093/cid/ciy235.

  PMID: 29590311 DERIVED

MeSH Terms

Conditions

Malaria, Vivax

Interventions

Primaquine

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Rose McGready, MD

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2012
• First Posted: January 31, 2013
• Study Start: December 1, 2012
• Primary Completion: July 1, 2014
• Study Completion: December 1, 2014
• Last Updated: February 15, 2016

Record last verified: 2016-02

Locations

TH (1)