Pharmacokinetics of piperaquine when used as malaria chemoprevention in HIV-infected children on antiretroviral therapy in Uganda

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American Association of Pharmaceutical Scientists (AAPS), PharmSci 360, Advancing Pharmaceutical Sciences, Careers, and Community

Authors

Richard Kajubi1, Malik Koire2, Meghan Whalen3, Florence Marzan3, Xay Pham3, Justin Goodwin4, Martina Wade4, Kacey Richards4, Grace Kisitu2, Francesca Aweeka3, Liusheng Huang3, Norah Mwebaza1, Sunil Parikh4

  1. Infectious Diseases Research Collaboration, Kampala, Uganda.
  2. Baylor College of Medicine, Kampala, Uganda.
  3. University of California, San Francisco, San Francisco, CA, United States.
  4. Yale School of Public Health, New Haven, CT, United States.

Contact information

Richard Kajubi
Dept. of Pharm. at MUK
+256776211591
[email protected]

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Introduction

  • Dihydroartemisinin-piperaquine (DHA-PPQ) is increasingly used for malaria treatment and considered for malaria chemoprevention.

  • These regions are often co-endemic for both malaria and HIV.

  • PPQ is metabolized by cytochrome p450 CYP3A4 leading to drug-drug interactions (DDI) between DHA-PPQ and antiretroviral therapy when co-administered.

  • Suboptimal or elevated pharmacokinetic (PK) exposure may result with efavirenz (EFV)- and lopinavir/ritonavir (LPV/r)-based antiretroviral therapy, respectively, compromising efficacy, toxicity, and risking the emergence and/or spread of drug resistance.

  • Dolutegravir (DTG), which is currently the most widely used antiretroviral in sub-Saharan Africa, has not been extensively evaluated for DDIs.

Method

Clinical trial design

We conducted a prospective open-label PPQ PK study in the context of EFV-, LPV/r- and DTG-based antiretroviral regimens among HIV-infected Ugandan malaria-uninfected children alongside HIV-uninfected controls. (Figure 1). DHA-PPQ was given once daily for 3 days at the WHO weight-based recommended dose.

diagram compares children 3 to 10 years old with those 11 to 17 years old, all groups undergo PK sampling post last dose.

Figure 1. Study population

Determination of PPQ concentration

A validated LC-tandem mass method was used to determine [PPQ]1. The calibration range was 0.5- 250 ng/mL.

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, Tmax, Thalf, AUC0-21d, AUC0-28d, and AUC0-42d were calculated for comparison. STATA version SE14.1 was used for the statistical analyses.

Results

Two control groups were used: the older children for DTG and younger children for LPV/r and EFV (Table 1). PK data are shown in Table 2-3 and Figure 2. The box plot for day 28 and 42 PPQ are shown in Figure 3 and 4.

Table 1. Demographic data of study participants
 

Controls

Concomitant ART
 

10-17yr (n=30)

3-10yr (n=30)

DTG (n=30)

LPV/r (n=30)

EFV (n=30)

Age (yr) Median (IQR)

15 (13.8 – 16.3)

7.4 (6.0 – 8.7)

15.3 (13.6 - 17.1)

7.1 (6.0 – 8.7)

7.9 (6.6 – 9.1)

Weight (kg) Median (IQR)

42.4 (35.4 – 53.5)

23.6 (21.4 – 27.9)

48.7 (38.7 – 53.4)

19 (17.4 – 22.5)

21.4 (18 – 26.2)

Height (cm) Median(IQR)

152.5 (148.8 – 160.3)

123 (118.8 – 130.3)

154 (147.8 – 163.3)

115 (108.2 – 123.6)

119.8 (112.3 – 128.4)

BMI (kg/m2)

Median (IQR)

18.1 (16.1 – 19.6)

15.6 (14.9 – 16.3)

20 (12.9 – 20.8)

14.8 (14.4 – 15.1)

15.1 (14.6 – 15.8)

Hemoglobin (g/dL)

12.7 (12.0 – 13.6)

11.9 (10.8 – 12.7)

13.8 (12.6 – 15.5)

12.9 (11.8 - 13.6)

12.5 (11.9 – 13.0)

Male n (%)

13 (43.3)

19 (63.3%)

17(56.7%)

15 (50%)

11 (36.7)

DHA (mg/kg/dose)

2.2 (1.7 - 3.4)

2.7 (2.4 - 3.8)

2.4 (1.7 - 3.1)

3.0 (2.4-3.5)

3.1 (2.5 - 3.5)

Total weight adjusted DHA (mg/kg)

6.5 (5.2 - 10.2)

8.2 (7.1 - 11.4)

7.3 (5.0 - 9.4)

8.9 (7.1 -10.5)

9.2 (7.4 - 10.5)

PQ (mg/kg/dose)

17.4 (13.9 - 27.3)

22.0 (18.9 - 30.5)

19.4 (13.2 - 25.1)

23.6 (18.9 - 27.9)

24.7 (19.7 - 28.1)

Total weight adjusted PQ (mg/kg)

52.2 (41.7 - 81.8)

65.9 (56.8 - 91.4)

58.2 (39.7 - 75.2)

70.9 (56.8 - 83.7)

74.0 (59.0 - 84.2)
Table 2. PK parameters of piperaquine in children in the context of DTG-based antiretroviral therapy

PK parameters

HIV+ children
(DTG)
GM; 90%CI (n=30)

HIV- children
Control
GM; 90%CI (n=30)

GMR

P value

Cmax, ng/mL

285 (224, 363)

272 (221, 334)

1.05

0.73

Tmax, hr

3.04 (2.94, 6.02)

4.02 (3.00, 6.05)

1.320

0.16

t1/2,hr*

434 (386, 487)

400 (346, 461)

1.090

0.4

AUC0-day21, hr·ng/mL

11.5 (9.24, 14.3)

14.7 (12.5, 17.2)

0.782

0.16

AUC0-day28, hr·ng/mL

12.7 (10.3, 15.7)

16.4 (14.1, 19.1)

0.774

0.13

AUC0-day42, hr·ng/mL

14. 9(12.0, 18.2)

19.2 (16.6, 22.2)

0.776

0.1

C7d_cap, ng/mL

39.1 (31.8, 48.0)

37.2 (29.4, 47.0)

1.050

0.68

C21d_cap, ng/mL

14.0 (11.8, 16.5)

18.1 (15.5, 21.1)

0.773

0.081

C28d_ven, ng/mL

5.44(4.23, 6.68)

8.01 (6.90, 9.30)

0.679

0.0199

C42d_ven, ng/mL

5.01 (4.12, 6.10)

13.8 (11.0, 17.2)

0.363

<0.0001

Note: GM: geometric mean; CI: confidence interval; GMR: geometric mean ratio (DTG/control); * n=29 for DTG and 26 for control. Tmax was median (IQR).

Table 3. PK parameters of piperaquine in children in the context of LPV/r- and EFV-based antiretroviral therapy.
 

HIV+ children

HIV- children

GMR (p value)
 

EFV (n=30)*

LPV (n=30)

Control (n=30)

EFV/control

LPV/control

PK parameters

GM; 90%CI

GM; 90%CI

GM; 90%CI

    

Cmax, ng/mL

243 (202, 292)

491 (397, 608)

218 (175, 272)

1.11 (0.53)

2.25 (0.0001)

Tmax, hr

4.02 (2.97, 6.05)

3.04 (2.00, 6.02)

3.00 (2.98, 6.10)

1.34 (0.41)

1.01 (0.98)

t1/2, hr**

209 (179, 244)

414 (364, 471)

435 (377, 502)

0.480 (<0.0001)

0.952 (0.49)

AUC0-day21, hr·ng/mL

4.17 (3.56, 4.88)

36.7 (30.7, 44.0)

11.2 (9.71, 12.9)

0.372 (<0.0001)

3.28 (<0.0001)

AUC0-day28, hr·ng/mL

4.33 (3.71, 5.06)

41.6 (34.8, 49.9)

12.5 (10.9, 14.4)

0.346 (<0.0001)

3.33 (<0.0001)

AUC0-day42, hr·ng/mL

4.47 (3.83, 5.22)

49.7 (41.7, 59.2)

14.6 (12.7, 16.7)

0.306 (<0.0001)

3.40 (<0.0001)

C7d_cap, ng/mL

8.16 (6.88 (9.69)

119 (96.2, 146)

28.7 (24.4, 33.7)

0.284 (<0.0001)

4.15 (<0.0001)

C21d_cap, ng/mL

2.24 (1.76, 2.88)

47.0 (37.7, 58.6)

14.9 (12.9, 17.1)

0.150 (<0.0001)

3.15 (<0.0001)

C28d_ven, ng/mL

1.03 (0.873, 1.22)

17.6, 13.6, 22.8)

6.41 (5.38, 7.65)

0.161 (<0.0001)

2.75 (<0.0001)

C42d_ven, ng/mL

0.757 (0.645, 0.888)

17.8 (14.9, 21.3)

9.34 (7.35, 11.9)

0.081 (<0.0001)

1.91 (0.0006)

two charts compare PQ concentration against time after 3rd dose (hr).

Figure 2. Mean plasma concentration versus time profile for PPQ in children. Top panel: Control (black line), DTG (green line). Bottom panel: Control (black line), LPV/r (green line) EFV (red line), data represent geometric mean, error bars represent 95% confidence interval.

box chart day 28 against groups 10, 11, 20, 21, and 22.

Figure 3. Box plot of day-28 PPQ in children receiving DHA-PPQ as chemoprevention with concomitant antiretroviral regimens. CT (11-17 yr), DTG controls; DTG, dolutegravir; CT (3-10yr), controls for LPV/r and EFV; LPV/r, lopinavir/ritonavir; EFV, efavirenz.

box chart day 42 against groups 10, 11, 20, 21, and 22.

Figure 4. Box plot of day-42 PPQ in children receiving DHA-PPQ as chemoprevention with concomitant antiretroviral regimens. CT (11-17 yr), DTG controls; DTG, dolutegravir; CT (3-10yr), controls for LPV/r and EFV; LPV/r, lopinavir/ritonavir; EFV, efavirenz.

Conclusions

  1. DTG did not impact PPQ total exposure but decreased terminal PPQ exposure by 1.3- to 2.8-fold.

  2. LPV/r increased total PPQ exposure by 3.3 fold and increased terminal PPQ by 2- to 4-fold.

  3. EFV decreased total PPQ exposure by 3-fold and decreased terminal PPQ even more significantly by 7- to 10-fold.

  4. The impact of DTG and EFV on terminal PPQ increased over time, but the impact of LPV/r on terminal PPQ diminished over time.

  5. HIV-infected children on EFV- and LPV/r-based antiretroviral regimens have opposing effects on PQ exposure, which may impact efficacy and toxicity, respectively, while reductions in the terminal PQ exposure in those on DTG may reduce the duration of post-treatment malaria chemoprophylaxis.

References and Funding

  1. Determination of the antimalarial drug piperaquine in small volume pediatric plasma samples by LC–MS/MS (PDF, 18 pages). Kjellin, et al. Bioanalysis, 2014, 6 (23):3081-3089.

This work was supported by the National Institutes of Health (R01 HD068174).

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