Pharmacometric assessment of primaquine induced haemolysis in glucose-6-phosphate dehydrogenase deficiency

Public Review:

In countries endemic for P vivax the need to administer a primaquine (PQ) course adequate to prevent relapse in G6PD deficient persons poses a real dilemma. On one hand PQ will cause haemolysis; on the other hand, without PQ the chance of relapse is very high. As a result, out of fear of severe haemolysis, PQ has been under-used.

In view of the above, the Authors have investigated in well-informed volunteers, who were kept under close medical supervision in hospital throughout the study, two different schedules of PQ administration: (1) escalating doses (to a total of 5-7 mg/kg); (2) single 45 mg dose (0.75 mg/kg).

It is shown convincingly that regimen (1) can be used successfully to deliver within 3 weeks, under hospital conditions, the dose of PQ required to prevent P vivax relapse.

As expected, with both regimens acute haemolytic anaemia (AHA) developed in all cases. With regimen (2), not surprisingly, the fall in Hb was less, although it was abrupt. With regimen (1) the average fall in Hb was about 4 G. Only in one subject the fall in Hb mandated termination of the study.

Since the data from the Chicago group some sixty years ago, there has been no paper reporting a systematic daily analysis of AHA in so many closely monitored subjects with G6PD deficiency. The individual patient data in the Supplementary material are most informative and more than precious.

Having said this, I do have some general comments.
1. Through their remarkable Part 1 study, the Authors clearly wish to set the stage for a revision of the currently recommended PQ regimen for G6PD deficient patients. They have shown that 5-7 mg/kg can be administered within 3 weeks, whereas the currently recommended regimen provides 6 mg/kg over no less than 8 weeks.
2. Part 2 aims to show that, as was known already, even a single PQ dose of 0.75 mg/kg causes a significant degree of haemolysis: G6PD deficiency-related haemolysis is characteristically markedly dose-dependent. Although they do not state it explicitly in these words (I think they should), the Authors want to make it clear that the currently recommended regimen does cause AHA.
3. Regulatory agencies like to classify a drug regimen as either SAFE or NOT-SAFE; they also like to decide who is 'at risk' and who is 'not at risk'. A wealth of data, including those in this manuscript, show that it is not correct to say that a G6PD deficient person when taking PQ is at risk of haemolysis: he or she will definitely have haemolysis. As for SAFETY, it will depend on the clinical situation when PQ is started and on the severity of the AHA that will develop.

The above three issues are all present in the discussion, but I think they ought to be stated more clearly.

Finally, by the Authors' own statement on page 15, the main limitation is the complexity of this approach. The authors suggest that blister packed PQ may help; but to me the real complexity is managing patients in the field versus the painstaking hospital care in the hands of experts, of which volunteers in this study have had the benefit. It is not surprising that a fall in Hb of 4 g/dl is well tolerated by most non-anaemic men; but patients with P vivax in the field may often have mild to moderate to severe anaemia; and certainly they will not have their Hb, retics and bilirubin checked every day. In crude approximation, we are talking of a fall in Hb of 4 G with regimen (1), as against a fall in Hb of 2 G with regimen (2), that is part of the currently recommended regimen: it stands to reason that, in terms of safety, the latter is generally preferable (even though some degree of fall in Hb will recur with each weekly dose). In my view, these difficult points should be discussed deliberately.