3TC), an NRTI.
DOVATO tablets are for oral administration. Each film-coated tablet contains the activeingredients 50 mg of dolutegravir (equivalent to 52.6 mg dolutegravir sodium) and 300 mg oflamivudine and the inactive ingredients magnesium stearate, mannitol, microcrystallinecellulose, povidone K29/32, sodium starch glycolate, sodium stearyl fumarate. The tablet filmcoatingcontains the inactive ingredients hypromellose, polyethylene glycol, titanium dioxide.
Dolutegravir
The chemical name of dolutegravir sodium is sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2Hpyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate.
The empirical formula is C20H18F2N3NaO5and the molecular weight is 441.36 g/mol. It has the following structural formula:
Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water.
Lamivudine
The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine.
Lamivudine has also been referred to as (-)2,3-dideoxy, 3-thiacytidine. It has a molecularformula of C8H11N3O3S and a molecular weight of 229.3 g/mol. It has the following structuralformula:
Lamivudine is a white to off-white crystalline solid and is soluble in water.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
DOVATO is a fixed-dose combination of the HIV-1 antiretroviral agents, dolutegravir andlamivudine [see Microbiology (12.4)].
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of combination therapy as DOVATO or lamivudine given alone on the QT intervalhas not been studied. At a 250-mg suspension dose (exposures approximately 3–fold that of the50-mg once-daily dose at steady state), dolutegravir given alone did not prolong the QTc intervalto any clinically relevant extent.
Effects of Dolutegravir on Renal Function
No clinically significant dolutegravir exposure-response relationship on the glomerular filtrationrate or effective renal plasma flow was observed. The effect of dolutegravir on renal functionwas eva luated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthysubjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twicedaily (n = 13), or placebo once daily (n = 12) for 14 days.
12.3 Pharmacokinetics
The Cmax, Ctrough, and AUCtau parameters of the components of DOVATO are provided in Table6.
Table 6. Multiple-Dose Pharmacokinetic Parameters of the Components of DOVATO
Parameter Mean (%CV) Dolutegravira Lamivudineb
Cmax (mcg/mL) 3.67 (20%) 2.04 (26%)
Ctrough (mcg/mL) 1.11 (46%) 0.042 (38%)
AUCtau (mcg/h/mL) 53.6 (27%) 8.87 (21%)
a Based on dolutegravir 50-mg once-daily dosage administered to antiretroviral (ART) treatmentnaive
adults.
b Based on lamivudine 300-mg once-daily dosage administered to healthy subjects.
Cmax = Maximum concentration; Ctrough = Lowest concentration before administration of the nextdose; AUCtau = Area under the concentration-time curve integrated across the dosing interval.
The absorption, distribution, and elimination pharmacokinetic parameters of the components ofDOVATO are provided in Table 7.
Table 7. Pharmacokinetic Properties of the Components of DOVATO
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