Raltegravir pharmacokinetic targets met in high-risk HIV-exposed infants

Daily raltegravir was safe and well tolerated at six weeks of life and met pharmacokinetic targets in HIV-exposed infants, according to data from IMPAACT P1110 presented at CROI 2017.

Previous studies have shown raltegravir (RAL) elimination to be highly variable in the first weeks of life due to low UGT1A1 activity.

IMPAACT P1110 is a phase I multicentre study in full-term HIV-1 exposed neonates at high risk of HIV with or without maternal RAL exposure. It includes two cohorts: cohort 1 infants received two single RAL doses one week apart; cohort 2 infants received daily RAL dosing for first six weeks of life.

PK data from cohort 1 and from older infants and children in IMPAACT P1066 were combined in a population PK model. The model included maturation of absorption rate from 16% of max at birth to 90% at two weeks, and clearance from close to nil to max at approximately six months of age.

The model was used to perform simulations of possible daily dosing regimens for RAL-naive infants in cohort 2 (using oral granules for suspension). See Table 1.

Table 1: Raltegravir dosing in IMPAACT P1110
Days of life	Dose mg/kg	Frequency
1-7	1.5	Once daily
8-28	3.0	Twice daily
after 28	6.0	Twice daily

Table 1: Raltegravir dosing in IMPAACT P1110

Days of life

Dose mg/kg

Frequency

1-7

1.5

Once daily

8-28

3.0

Twice daily

after 28

6.0

Twice daily

Plasma samples were collected at the following time points. First dose: pre-dose, 1-2, 6-10 and 20-24 hours post dose. Second dose: 3-6 hours post dose. Day 6-9 of life: pre-dose. Day 15-18 of life: pre-dose, 4-6 and 8-12 hours post-dose. Day 28-32 of life: pre-dose. Week 5-6 of life: pre-dose and 3-6 hours post-dose.

Exposure targets are: AUC24 12-40 mg*h/L; AUC12 6-20 mg*h/L; C12 or C24 > 33 ng/mL; and Cmax <8724 ng/mL.

Cohort 2 enrolled 26 infants: 46% female; 69% black, 12% white and 19% other; median gestation age 38.5 weeks and birth weight 2.93 kg. Evaluable PK and 6-week safety data were available for 25 infants.

The investigators reported no drug related adverse events. All RAL exposure targets were met; PK parameters are shown in Table 2.

Table 2: Raltegravir PK parameters IMPAACT 1110
	After initial dose: 1.5 mg/kg once daily (n=25)	Day 15-18: 3.0 mg/kg twice daily (n=24)
Geometric mean (CV)	Target	Geometric mean (CV)	Target
AUC (mg*h/L)	38.2 (38.4%)	11 above 13 met 0 below	14.3 (43.3%)	8 above 14 met 1 below
Trough (ng/mL)	948 (64.2%)	25 above 0 below	176 (93.8%)	22 above 1 below
Cmax (mg/mL)	2350 (35.0%)	0 above 25 below	2850 (41.9%)	0 above 24 below
Tmax (mg/mL)	5.4 (57.5%)		5.4 (57.5%)
T1/2 (hours)	15.8 (174.8%)		15.8 (174.8%)

Table 2: Raltegravir PK parameters IMPAACT 1110

After initial dose: 1.5 mg/kg once daily (n=25)

Day 15-18: 3.0 mg/kg twice daily (n=24)

Geometric mean (CV)

Target

Geometric mean (CV)

Target

AUC (mg*h/L)

38.2 (38.4%)

11 above 13 met 0 below

14.3 (43.3%)

8 above 14 met 1 below

Trough (ng/mL)

948 (64.2%)

25 above 0 below

176 (93.8%)

22 above 1 below

Cmax (mg/mL)

2350 (35.0%)

0 above 25 below

2850

(41.9%)

0 above 24 below

Tmax (mg/mL)

5.4 (57.5%)

T1/2 (hours)

15.8 (174.8%)

The investigators noted that after the initial dose some infants had AUC24 slightly above target range – but they considered this to be acceptable given the rapid increase in RAL metabolism over the first week of life.

Infants born to mothers who received RAL and low birth weight infants are to be studied in IMPAACT P1110.