Modelling primaquine-induced haemolysis in G6PD deficiency

  1. James Watson  Is a corresponding author
  2. Walter RJ Taylor
  3. Didier Menard
  4. Sim Kheng
  5. Nicholas J White
  1. Mahidol University, Thailand
  2. University of Oxford, United Kingdom
  3. Institut Pasteur du Cambodge, Cambodia
  4. National Center for Parasitology, Entomology and Malaria Control, Cambodia
10 figures, 1 video, 2 tables and 2 additional files


Comparison between the data from Kheng et al. (2015) (shown in green, population median in thick black line) and posterior predictive 80% credible intervals (shown in red, median: thick line; 10&90% boundaries: dashed lines) in which adult Cambodian patients who were G6PD deficient were given weekly primaquine (45 mg) for eight weeks.

Left: reticulocyte response; Right: haemoglobin response.
Comparison between approximate model fits (red) and data (green) extracted from four primaquine studies with a single dose or daily regimens all at 30/45 mg adult doses.

Dosing periods are shaded in blue. The top two plots are for Mahidol and Viangchan variants, respectively. The bottom two plots are for the Mediterranean variant. From top left to bottom right: single 45 mg dose given to 7 G6PDd Mahidol Thais (Charoenlarp et al., 1972); 14 daily doses of 30 mg given to 15 G6PDd presumed Viangchan variant Khmer soldiers (only mean and extreme values reported) (Everett et al., 1977); 1 G6PDd Med Sardinian given two courses of daily 30 mg doses (Pannacciulli et al., 1965); 2 G6PDd Med Sardinians given 5 daily doses of 30 mg (Salvidio et al., 1967).
Comparison between approximate model fits (red) and data (green) extracted from four primaquine studies on the same individual with G6PDd African A-(Alving et al., 1960).

Dosing periods are shaded in blue. The top two plots are for weekly dosing regimens (8 doses): left is 60 mg per week; right is 45 mg per week; the bottom two plots are daily dosing regimens (14 doses): left is 15 mg per day; right is 30 mg per day.
Time series data of reticulocyte count (top row) and haemoglobin concentrations (bottom row) from the Cambodian study on G6PDd individuals (n=18, left column) and G6PD normals (n=57, right column) (Kheng et al., 2015).

The faint green lines show individual patient data; the thick black lines represent the population median values at each time-point; the dashed black lines show the interquartile range.
Figure 4—source data 1

This provides the source data for the reticulocyte counts and haemoglobin concentrations over time from the Kheng et al. (2015) study on weekly high-dose primaquine.
Estimating the dose-response curve for moderate/severe G6PDd.

Left: estimates of the logd parameter as a function of the administered dose plotted with a linear regression curve (red cross: Viangchan; red circles: posterior estimates from model fitted to data from G6PDd Viangchan; blue cross: Mahidol; green crosses: African A-). Right: dose-response curve (thick black line) with 90% credible intervals (dotted black lines) as measured by fall in haemoglobin (y-axis) after five days at a given dose (x-axis) based on draws from the posterior distribution. The red and green crosses are the estimated falls after five days from Viangchan and African A- studies, respectively (see Figures 2,3). The red triangles show the falls observed in G6PDd Med studies from Figure 2.
Comparison of two 20-day ascending-dose regimens.

Left: haemolysis over time resulting from regimens. Blue: simplified regimen; red: idealized optimal regimen. Right: daily dosing construction for the two regimens. Total dose of blue regimen is 375 mg; total dose of red regimen is 382.5 mg.
Dynamics of ascending regimens.

Left: Comparing the haemolytic effect of four regimens. Thick black line: proposed optimal regimen; thick black dashed line: more conservative regimen with lower total dose; thin black dashed line: longer duration regimen for more severe variants; thick red line: bad choice regimen. Right: Posterior predictions for the proposed ascending dose for a given starting haemoglobin (steady state). Prediction using the median posterior values is shown by a thick black line. Predictions for 100 random draws from the posterior are shown by dashed blue lines. The horizontal line at a haemoglobin concentration of 9 is a proposed conservative ‘safety threshold’. Horizontal line at a haemoglobin concentration of 8 is a proposed regimen limiting toxicity threshold.
Appendix 1—figure 1
Posterior distributions of model parameters and hyperparameters.
Appendix 1—figure 2
Relationship between the steady state haematocrit and the mean corpuscular volume at day zero.

G6PDd patients are colored in blue, G6PD normal patients in red; women are shown by circles, men by triangles.
Appendix 1—figure 3
Individual parameter effects on the behavior of the compartmental model as shown by the haematocrit response and the reticulocyte count response.

From top left to bottom right, grouped by pairs: the mid-haemoglobin concentration parameter Hb50R for the reticulocyte release function; the mid-haemoglobin concentration parameter Hb50ρ for the marrow production function; the hill coefficient k for the reticulocyte release function; the max-fold production factor ρmax. The different values plotted for each parameter are shown in the legend for reticulocyte response plot.


Video 1
Animated video showing the red blood cell dynamics for our optimal ascending dose regimen.


Table 1

Illustrative regimens. A is our proposed optimal ascending dose regimen; B is a slight variation on this regimen (accelerated); C is a slower ascending dose regimen (potentially suitable for more severe variants); D illustrates a very poor regimen.
A7.5 mg15 mg22.5 mg30 mg--
B7.5 mg x3 d;10 mg x 2 d15 mg x 3 d; 17.5 mg x 2 d20 mg22.5 mg x 3 d; 25 mg x 2 d--
C5 mg10 mg15 mg20 mg25 mg-
D5 mg5 mg x 2 d; 10 mg x 3 d10 mg x 4 d; 15 mg x 1 d15 mg15 mg x 1d; 30 mg x 4d30 mg x 3 d
Table 2

Parameters and functions of the compartmental model along with their interpretation.
dunitlessParameter of age-dependent killing function.
HbHbSteady state haemoglobin concentration.
HbtHbHaemoglobin concentration at time t.
ρ(Hb)unitlessFold-increase in production of RBCs as a function of haemoglobin concentration (at steady state ρ(Hb)=1).
ρmaxunitlessMaximum fold increase in RBC production, this will be reduced in anemia.
Hb50ρHbHaemoglobin concentration for which production is elevated to ρmax/2.
Release(Hbt)daysTime of release of reticulocytes into circulation as a function of haemoglobin concentration.
kunitlessHill coefficient of sigmoid function Release(Hbt).
Hb50RHbHaemoglobin concentration corresponding to the mid-point of sigmoid describing reticulocyte release into circulation.
TminhoursEarliest age of an RBC vulnerable to primaquine-induced haemolysis.
TlaghoursTime to reach the maximum haemolytic effect of primaquine.

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  1. James Watson
  2. Walter RJ Taylor
  3. Didier Menard
  4. Sim Kheng
  5. Nicholas J White
Modelling primaquine-induced haemolysis in G6PD deficiency
eLife 6:e23061.