Introduction: Adherence to primaquine (PQ) for radical cure of Plasmodium vivax is affected by its poor tolerability. We quantified the relationship between the daily mg/kg dose of PQ, gastro-intestinal (GI) tolerability and haematological safety.
Methods: Clinical efficacy studies of patients with uncomplicated P. vivax including an arm with PQ, published between January 2000 and March 2021, were identified and individual patient data were pooled. GI intolerance was defined as the presence of vomiting, diarrhoea or anorexia between days 2-14. The effect of daily mg/kg PQ dose on tolerability was investigated using logistic regression. The proportion of patients developing a haematological adverse event (defined as haemoglobin drop between days 2-14, of ≥25% from baseline to <7g/dL) was determined.
Results: Individual-level data about GI tolerance were available from 3967 patients enrolled into 10 studies. Low dose PQ (<0.375 mg/kg/day) was administered to 1470 patients, intermediate dose (≥0.375 to <0.75 mg/kg/day) to 2836 patients and high dose (≥0.75 mg/kg/day) to 1512 patients; 1470 patients did not receive PQ. GI intolerance was reported by 25% of patients. Compared to patients not treated with PQ, the odds ratios (ORs) for GI intolerance were 1.40 (95% CI 0.92-2.13) for low dose, 1.59 (1.20-2.11) for intermediate dose and 2.29 (1.72-3.06) for high dose. The incidence of severe haematological events was 0.7% (10/1422) of patients treated with a high dose, 0.2% (4/1731) with an intermediate dose, 0% (0/1202) of patients with a low dose and 0.1% (1/1218) of those not treated with PQ. Of the 15 patients experiencing a severe haematological event, 10 patients had G6PD activity >30%, with activity in the other 5 patients unknown.
Conclusion: Higher daily PQ doses are associated with poorer GI tolerability. Severe haematological events are greater in the high dose group, though further studies are warranted to delineate this by G6PD status.