Pharmacokinetic Parameters Dolutegravir Lamivudine
Absorption
Tmax (h), mediana
2.5 1
Effect of Food
High-fat mealb
(relative to fasting) No clinically significant differences in the
pharmacokinetics of either component (after
administration of DOVATO) were observedc
Distribution
Plasma protein bindingd Approximately 99% 36%
Blood-to-plasma ratio 0.44 - 0.54 1.1 - 1.2
Elimination
t1/2 (h) Approximately 14 13 - 19
Metabolism
Metabolic pathways UGT1A1 (primary)
CYP3A (minor)
Not significantly
metabolized
Excretion
Major route of elimination Metabolism Renal, by OCT
system
Urine (unchanged) 31% (<1%)e Approximately 70%f
Feces (unchanged) 64% (53%)e −
a After administration of DOVATO (fasted state).
b High-fat meal is approximately 900 kcal, 56% fat.
c The geometric mean (90% confidence interval) AUC ratio (fed/fasted) of dolutegravir and
lamivudine is 1.33 (1.18, 1.48) and 0.91 (0.87, 0.96), respectively.
d Based on in vitro data.
e Based on single-dose, mass balance study of radiolabeled dolutegravir.
f Based on 24-hour urine collection obtained after oral or IV administration.
Tmax = Time to maximum concentration (Cmax); t1/2 = Elimination half-life.
Specific Populations
No clinically significant differences in the pharmacokinetics of the components of DOVATOwere observed based on age, sex, or race. Pharmacokinetic data for dolutegravir and lamivudinein subjects aged 65 years and older are limited. The effect of renal or hepatic impairment on thepharmacokinetics of DOVATO is unknown.
Drug Interaction Studies
Clinical Studies: No drug interaction studies were conducted with DOVATO. The druginteraction studies described below were conducted with dolutegravir or lamivudine when used
alone. Table 8 summarizes the effects of dolutegravir on the pharmacokinetics of coadministered
drugs. Table 9 summarizes the effect of other drugs on the pharmacokinetics of dolutegravirwhen used alone and Table 10 summarizes the effect of sorbitol on the pharmacokinetics oflamivudine when used alone.
Table 8. Effect of Dolutegravir on the Pharmacokinetics of Coadministered DrugsCoadministered Drug(s)
and Dose(s)
Dose of
Dolutegravir
Geometric Mean Ratio (90% CI) of
Pharmacokinetic Parameters of
Coadministered Drug with/without
Dolutegravir
No Effect = 1.00
Cmax AUC Ctau or C24
Daclatasvir
60 mg once daily
50 mg
once daily
1.03
(0.84 to 1.25)
0.98
(0.83 to 1.15)
1.06
(0.88 to 1.29)
Ethinyl estradiol
0.035 mg
50 mg
twice daily
0.99
(0.91 to 1.08)
1.03
(0.96 to 1.11)
1.02
(0.93 to 1.11)
Grazoprevir
200 mg once daily
50 mg
single dose
0.64
(0.44, 0.93)
0.81
(0.67, 0.97)
0.86
(0.79, 0.93)
Metformina
500 mg twice daily
50 mg
once daily
1.66
(1.53 to 1.81)
1.79
(1.65 to 1.93)
_
Metformina
500 mg twice daily
50 mg
twice daily
2.11
(1.91 to 2.33)
2.45
(2.25 to 2.66)
_
Methadone
16 to 150 mg
50 mg
twice daily
1.00
(0. 94 to 1.06)
0.98
(0.91 to 1.06)
0.99
(0.91 to 1.07)
Midazolam
3 mg
25 mg
once daily
_ 0.95
(0.79 to 1.15)
_
Norelgestrominb
0.25 mg
50 mg
twice daily
0.89
(0.82 to 0.97)
0.98
(0.91 to 1.04)
0.93
(0.85 to 1.03)
Sofosbuvir
400 mg once daily
Metabolite (GS-33 |
