Unbound piperaquine exposure in children and pregnant women receiving dihydroartemisinin-piperaquine as malaria chemoprevention
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Web version
American Association of Pharmaceutical Scientists (AAPS)5, PharmSci 3606, Advancing Pharmaceutical Sciences, Careers, and Community
Authors
Usman Aslam-Mir1, Howard Hong1, Xay Pham1, Richard Kajubi2, Meghan E. Whalen1, Norah Mwebaza2, Erika Wallender1, Grant Dorsey1, Philip J. Rosenthal1, Francesca T. Aweeka1, Liusheng Huang1
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University of California, San Francisco, San Francisco, CA, United States.
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Infectious Diseases Research Collaboration, Kampala, Uganda.
Contact information
Liusheng Huang, PhD7
UCSF Department of Clinical Pharmacy
415-502-2594
liusheng.huang@ucsf.edu8
Jump below to
- Introduction9
- Method10
- Results11
- Conclusions12
- References13
Introduction
Figure 1. Active sites of piperaquine. Source: DOI:10.4155/fmc.13.113.
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Dihydroartemisinin-piperaquine has been studied for malaria prevention due to the long elimination half-life of piperaquine (PPQ).
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Only unbound PPQ transverses biological membranes and exerts pharmacological effects at active sites-- digestive vacuole (the yellow core in Figure 1). PPQ is protonated and trapped in the acidic digestive vacuole.
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Mechanism of action: PPQ binds to heme Fe3+ in digestive vacuole to prevent hemozoin formation.
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Young children and pregnant women have distinct physiological conditions that may alter drug-protein binding.
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We previously reported a reduced exposure of PPQ (protein-bound and unbound) in children and pregnant women, but unbound PPQ exposure has not been studied.
Method
Clinical Trial design: The study was a part of a large study carried out between December 2014 and May 2017 in Tororo, Uganda. Enrollment for pharmacokinetic (PK) study is shown in Figure 2.
Figure 2. Study population.
Drug administration and PK sampling
Dihydroartemisinin-piperaquine was given once daily for 3 days at standard doses every 4 weeks or 8 weeks for malaria prevention. PK samples were collected post last dose at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 hr for unbound and total PQ determination in venous plasma.
Determination of unbound PPQ
unbound PPQ was separated from plasma with Microcon Ultracel centrifugal filter devices (NMWL 10k), mixed with IS (PPQ-d6) and injected into UPLC-MS/MS system (Figure 3). The calibration range was 20 – 5000 pg/mL.
Figure 3. unbound PPQ quantitation.
PK data analysis
Noncompartmental analysis was performed with Phoenix WinNonlin version 8.3.1 (Certara, Princeton, NJ) using the linear up- log down trapezoidal rule. PK parameters Cmax and AUC0-24h were calculated for both total and unbound PPQ for comparison. Fraction of unbound PPQ (fu) was calculated with each paired concentration (PPQunbound/PPQtotal). Stata version SE14.1 was used for the statistical analyses.
Results
HIV+ women were older than HIV- pregnant women (p<0.01) but their weights were similar, so the age difference is not expected to impact on drug-binding proteins. (Table 1). PK data for children are shown in Table 2 and Figure 4. PK data for pregnant women are shown in Table 3 and Figure 5. The fu is shown in Figure 6.
|
Children |
Pregnant women at 28 wk gestation |
Adults |
|||
|---|---|---|---|---|---|
|
32 wk (n=32) |
104 wk (n=31) |
HIV- (n=31) |
HIV+ (EFV, n=27) |
n=30 |
|
|
Age (yr) |
0.61 |
2 |
23 (18, 31) |
30 (18, 43)* |
24 (19, 32) |
|
Weight (kg) |
7.53 (6.01, 9.03) |
10.6 (8.37, 12.9) |
57.5 (45.2, 83,2) |
57.6 (43.7, 72.8) |
52.9 (38.5, 72.9) |
|
Height (cm) |
68 (62, 71) |
83 (77, 89) |
163 (150, 179) |
163 (147, 176) |
162 (148,174) |
|
BMI |
16.8 (13.0, 19.6) |
15.5 (13.8, 17.7) |
|||
|
Hemoglobin (g/dL) |
10.4 (8.6, 12) |
11.5 (9.7, 12.4) |
12.0 (10.3, 16.8) |
11.6 (8.1, 19.2) |
13.9 (11.8, 16.3) |
|
Female |
14 |
14 |
30 |
||
|
Male |
18 |
17 |
|||
|
Children |
||||||
|---|---|---|---|---|---|---|
|
32 weeks |
104 weeks |
Adult |
104 wk/32 wk |
32 week/adults |
104 week/adults |
|
|
PK parameters |
GM; 95%CI (n = 32) |
GM; 95%CI (n = 31) |
GM; 95%CI (n = 30) |
GMR (p value) |
GMR (p value) |
GMR (p value) |
Total PPQ |
||||||
|
Cmax, ng/mL |
345 (279, 427) |
309 (266, 359) |
497 (392, 630) |
0.896 (0.69) |
0.694 (0.0037) |
0.622 (0.0002) |
|
Tmax*, hr |
4.03 (3.06, 6.01) |
4.02 (2.03, 6.05) |
3.06 (2.07, 4.03) |
0.998 (0.21) |
1.32 (0.0085) |
1.31 (0.41) |
|
AUC0-24h, hr·µg/mL |
3.88 (3.24, 4.64) |
3.45 (3.04, 3.91) |
5.47 (4.41, 6.79) |
0.889 (0.29) |
0.709 (0.0034) |
0.631 (<0.0001) |
Unbound PPQ |
||||||
|
Cmax, ng/mL |
2.35 (1.84, 3.01) |
2.28 (1.90, 2.74) |
2.97 (2.29, 3.85) |
0.970 (0.95) |
0.791 (0.13) |
0.768 (0.043) |
|
Tmax*, hr |
3.03 (2.06, 4.42) |
3.05 (2.03, 4.1) |
3.08 (3.00, 4.07) |
1.01 (0.86) |
0.984 (0.83) |
0.990 (0.85) |
|
AUC0-24h, hr·ng/mL |
23.0 (18.5, 28.7) |
23.0 (19.5, 27.1) |
28.1 (21.7, 36.3) |
1.00 (0.978) |
0.819 (0.071) |
0.819 (0.041) |
|
fu (%)** |
0.658 (0.618, 0.701) |
0.718 (0.685, 0.753) |
0.520 (0.501,0.539) |
1.09 (0.0064) |
1.27 (<0.0001) |
1.38 (<0.0001) |
|
AUCfree/total (%) |
0.594(0.514, 0.686) |
0.666 (0.594, 0.746) |
0.513 (0.469, 0.560) |
1.12 (0.22) |
1.16 (0.13) |
1.30 (0.001) |
|
Pregnant alone (P) |
Preg+EFV |
Non-pregnant (NP) |
P/NP |
Preg+EFV/P |
Preg+EFV/NP |
|
|---|---|---|---|---|---|---|
|
PK parameters |
GM; 90%CI (n=31) |
GM; 90%CI (n=27) |
GM; 90%CI (n=30) |
GMR (p value) |
GMR (p value) |
GMR (p value) |
Total PPQ |
||||||
|
Cmax, ng/mL |
404 (332, 491) |
333 (277, 400) |
497 (392, 630) |
0.813 (0.13) |
0.824 (0.067) |
0.670 (<0.01) |
|
Tmax*, hr |
3.08 (3.00, 4.03) |
4.00 (2.03, 5.98) |
3.06 (2.07, 4.03) |
1.01 (0.71) |
1.30 (0.78) |
1.31 (0.65) |
|
AUC0-24h, hr·µg/mL |
4.58 (3.85, 5.44) |
3.77 (3.25, 4.38) |
5.49 (4.42, 6.81) |
0.834 (0.11) |
0.823 (0.019) |
0.687 (<0.01) |
Unbound PPQ |
||||||
|
Cmax, ng/mL |
2.41 (1.83, 3.19) |
2.40 (1.88, 3.07) |
2.97 (2.29, 3.85) |
0.811 (0.20) |
1.00 (0.95) |
0.808 (0.14) |
|
Tmax*, hr |
3.98 (3.02, 4.03) |
4.00 (2.98, 4.07) |
3.08 (3.00, 4.07) |
1.29 (0.71) |
1.01 (0.81) |
1.30 (0.72) |
|
AUC0-24, hr·ng/mL |
23.6 (18.8, 29.5) |
24.2 (19.1, 30.5) |
28.2 (21.8, 36.5) |
0.837 (0.12) |
0.975 (0.87) |
0.858 (0.13) |
|
fu (%)** |
0.533 (0.510, 0.557) |
0.641 (0.602, 0.682) |
0.520 (0.501,0.539) |
1.03 (0.66) |
1.20 (<0.01) |
1.23 (<0.01) |
|
AUCfree/total (%) |
0.515 (0.464, 0.570) |
0.640 (0.543, 0.754) |
0.514(0.471, 0.562) |
1.00(0.90) |
1.24 (<0.01) |
1.25 (<0.01) |
Figure 4. Mean plasma concentration versus time profile for PPQ in children aged 32 weeks (black line), the same children aged 104 weeks (red line), and the adults (green line). Error bars represent 95% confidence interval. Top, unbound PQ; bottom, total PQ.
Figure 5. Mean plasma concentration versus time profile for PPQ in HIV-infected pregnant women with concomitant EFV-based ART (red line), HIV-uninfected pregnant women (black line), and postpartum women (green line). Error bars represent 95% confidence interval. Top, unbound PPQ; bottom, total PPQ.
Figure 6. Box plot of fraction of unbound PPQ in children and pregnant women.104wk, children at 104 weeks of age; 32wk, children at 32 weeks of age; control, adult postpartum women. Preg_EFV, HIV infected pregnant women with concomitant efavirenz-based antiretroviral therapy; Pregnant, HIV uninfected pregnant women.
Conclusions
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Increased fraction of unbound PPQ in children partially compensated for reduction of total PPQ exposure.
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Increased fraction of unbound PPQ in the context of efavirenz partially compensated for reduction of total PPQ exposure. Data suggest binding site replacement drug-drug interaction.
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Dose adjustment only based on total PPQ exposure may not be accurate.
References
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Huang et al. J Chromatogr Open. 2022; 2: 100042.
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Kajubi et al. Clin Pharmacol Ther. 2017; 102(3): 520-528.
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Whalen et al. Clin Pharmacol Ther. 2019;106(6):1310-18.
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Hong et al. Antimicrob Agents Chemother. 2023, 67(4): e0142722.
This work was supported by the National Institutes of Health (R21 AI153848, 4P01HD059454, R01AI117001, and P30AI022763).
