DELSTRIGO (Page 5 of 10)

8.5 Geriatric Use

Clinical trials of doravirine, lamivudine, or TDF did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of DELSTRIGO in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF, both components of DELSTRIGO, cannot be altered, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage adjustment of DELSTRIGO is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. DELSTRIGO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

No data are available on overdose of DELSTRIGO in patients and there is no known specific treatment for overdose with DELSTRIGO. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

Doravirine: There is no known specific treatment for overdose with doravirine.

Lamivudine: Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

TDF: TDF is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

DELSTRIGO is a fixed-dose combination, film-coated tablet, containing doravirine, lamivudine, and TDF for oral administration.

Doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI).

Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine and is an HIV-1 nucleoside analogue reverse transcriptase inhibitor.

TDF (a prodrug of tenofovir) is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo TDF is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Tenofovir is an HIV-1 reverse transcriptase inhibitor.

Each tablet contains 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium stearyl fumarate. The tablets are film coated with a coating material containing the following inactive ingredients: hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. The coated tablets are polished with carnauba wax.

Doravirine:

The chemical name for doravirine is 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H -1,2,4-triazol-3-yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]benzonitrile.

It has a molecular formula of C₁₇ H₁₁ ClF₃ N₅ O₃ and a molecular weight of 425.75.

It has the following structural formula:

Doravirine is practically insoluble in water.

Lamivudine:

The chemical name for lamivudine is (-)-1-[(2R ,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-cytosine.

It has a molecular formula of C₈ H₁₁ N₃ O₃ S and a molecular weight of 229.26.

It has the following structural formula:

Lamivudine is soluble in water.

TDF:

The chemical name for TDF is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy] phosphinyl]- methoxy]propyl]adenine fumarate (1:1).

It has a molecular formula of C₁₉ H₃₀ N₅ O₁₀ P∙C₄ H₄ O₄ and a molecular weight of 635.52.

It has the following structural formula:

TDF is slightly soluble in water.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

DELSTRIGO is a fixed-dose combination of the antiretroviral drugs doravirine, lamivudine, and TDF [see Microbiology (12.4)].

12.2 Pharmacodynamics

In a Phase 2 trial evaluating doravirine over a dose range of 0.25 to 2 times the recommended dose of doravirine in DELSTRIGO (in combination with FTC/TDF) in HIV-1-infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine.

Cardiac Electrophysiology

At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose of doravirine in DELSTRIGO does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Single-dose administration of one DELSTRIGO tablet to healthy subjects provided comparable exposures of doravirine, lamivudine, and tenofovir to administration of doravirine tablets (100 mg) plus lamivudine tablets (300 mg) plus TDF tablets (300 mg). Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Pharmacokinetic properties of the components of DELSTRIGO are provided in Table 7.

Table 7: Pharmacokinetic Properties of the Components of DELSTRIGO

Parameter	Doravirine	Lamivudine	Tenofovir
Abbreviations: NA=not available; AUC=area under the time concentration curve; Cmax =maximum concentration; C24 =concentration at 24 hours; Tmax =time to Cmax ; Vdss =apparent volume of distribution at steady state; t1/2 =elimination half-life; CL/F=apparent clearance; CLrenal = renal clearance
* Presented as geometric mean (%CV: geometric coefficient of variation) or mean ± SD. † Doravirine 100 mg once daily to HIV-1-infected subjects. ‡ Lamivudine 300 mg once daily for 7 days to 60 healthy subjects. § Single 300 mg dose of TDF to HIV-1-infected subjects in the fasted state. ¶ Geometric mean ratio [high-fat meal/fasting] and (90% confidence interval) for PK parameters. High fat meal is approximately 1000 kcal, 50% fat. The effect of food is not clinically relevant. # Based on IV dose.
General
Steady State Exposure *
AUC0-24 (mcg∙h/mL)	16.1 (29)†	8.87 ± 1.83‡	2.29 ± 0.69§
Cmax (mcg/mL)	0.962 (19)†	2.04 ± 0.54‡	0.30 ± 0.09§
C24 (mcg/mL)	0.396 (63)†	NA	NA
Absorption
Absolute Bioavailability	64%	86%	25%
Tmax (h)	2	NA	1
Effect of Food ¶
AUC Ratio	1.10 (1.01, 1.20)	0.93 (0.84, 1.03)	1.27 (1.17, 1.37)
Cmax Ratio	0.95 (0.80, 1.12)	0.81 (0.65, 1.01)	0.88 (0.74, 1.04)
C24 Ratio	1.26 (1.13, 1.41)	NA	NA
Distribution
Vdss #	60.5 L	1.3 L/kg	1.3 L/kg
Plasma Protein Binding	76%	< 36%	<0.7%
Elimination
t1/2 (h)	15	5-7	17
CL/F (mL/ min)*	106 (35.2)	398.5 ± 69.1	1,043.7 ± 115.4
CLrenal (mL/ min)*	9.3 (18.6)	199.7 ± 56.9	243.5 ± 33.3
Metabolism
Primary Pathway(s)	CYP3A	Minor	No CYP Metabolism
Excretion
Major route of elimination	Metabolism	Glomerular filtration and active tubular secretion	Glomerular filtration and active tubular secretion
Urine (unchanged)	6%	71%	70-80%
Biliary/Fecal (unchanged)	Minor	NA	NA

Specific Populations

In adults, no clinically significant differences in the pharmacokinetics of certain DELSTRIGO components were observed based on age ≥65 years (for doravirine), sex (for doravirine, lamivudine, tenofovir), and race/ethnicity (for doravirine, lamivudine). The effects of age (≥65 years) on the pharmacokinetics of lamivudine and tenofovir, and the effect of race on the pharmacokinetics of tenofovir are unknown.

Patients with Renal Impairment

Doravirine: No clinically significant difference in the pharmacokinetics of doravirine were observed in subjects with mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault). Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis.

Lamivudine: The AUC_inf , C_max , and half-life of lamivudine increased and CL/F decreased to a clinically significant extent with diminishing renal function (CLcr 111 to < 10 mL/min).

TDF: A clinically significant increase in the C_max and AUC of tenofovir was observed in subjects with CLcr < 50 mL/min or with end stage renal disease requiring dialysis [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Doravirine: No clinically significant difference in the pharmacokinetics of doravirine was observed in subjects with moderate hepatic impairment (Child-Pugh score B) compared to subjects without hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C).

Lamivudine: No clinically significant differences in lamivudine pharmacokinetics were observed with diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.

TDF: No clinically significant differences in tenofovir pharmacokinetics were observed between subjects with any degree of hepatic impairment and healthy subjects.

Pediatric Patients

Mean doravirine exposures were similar in 54 pediatric patients aged 12 to less than 18 years and weighing at least 35 kg who received doravirine or DELSTRIGO in IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or DELSTRIGO. Exposures of lamivudine and tenofovir in pediatric patients following the administration of DELSTRIGO were similar to those in adults following administration of lamivudine and tenofovir (Table 8). For pediatric patients weighing ≥ 35 kg and < 45 kg who receive doravirine 100 mg or DELSTRIGO, the population pharmacokinetic model-predicted mean C₂₄ of doravirine was comparable to that achieved in adults, whereas mean AUC_0-24 and C_max of doravirine were 25% and 36% higher than adult values, respectively. However, the predicted AUC_0-24 and C_max increases are not considered clinically significant.

Table 8: Steady State Pharmacokinetics for Doravirine, Lamivudine, and Tenofovir Following Administration of Doravirine or DELSTRIGO in HIV-1-Infected Pediatric Patients Aged 12 to Less than 18 Years and Weighing at Least 35 kg

Parameter *	Doravirine †	Lamivudine ‡	Tenofovir ‡
Abbreviations: NA=not applicable; AUC=area under the time concentration curve; Cmax =maximum concentration; C24 =concentration at 24 hours
* Presented as geometric mean (%CV: geometric coefficient of variation) † From population PK analysis (n=53 weighing ≥45 kg, n=1 weighing ≥35 kg to <45 kg) ‡ From intensive PK analysis (n=10)
AUC0-24 (mcg•h/mL)	16.4 (24)	11.3 (28)	2.55 (14)
Cmax (mcg/mL)	1.03 (16)	2.1 (24)	0.293 (37)
C24 (mcg/mL)	0.379 (42)	NA	NA

Drug Interaction Studies

DELSTRIGO is a complete regimen for the treatment of HIV-1 infection; therefore, DELSTRIGO is not recommended to be administered with other HIV-1 antiretroviral medications. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided.

The drug interaction trials described were conducted with doravirine, lamivudine and/or TDF, as single entities; no drug interaction trials have been conducted using the combination of doravirine, lamivudine, and TDF. No clinically relevant drug interactions were observed between doravirine, lamivudine, and TDF.

Doravirine: Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine.

Doravirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Doravirine did not inhibit major drug metabolizing enzymes in vitro , including CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and UGT1A1 and is not likely to be an inducer of CYP1A2, 2B6, or 3A4. Based on in vitro assays, doravirine is not likely to be an inhibitor of OATP1B1, OATP1B3, P-glycoprotein, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2K. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration with other drugs on the exposure (C_max , AUC, and C₂₄ ) of doravirine are summarized in Table 9. A single doravirine 100 mg dose was administered in these studies unless otherwise noted.

Table 9: Drug Interactions: Changes in Pharmacokinetic Parameter Values of Doravirine in the Presence of Co-administered Drug

Co-administered Drug	Regimen of Co-administered Drug	N	Geometric Mean Ratio (90% CI) of Doravirine Pharmacokinetics with/without Co-administered Drug (No Effect=1.00)
			AUC *	Cmax	C24
CI = confidence interval; QD = once daily; BID = twice daily
* AUC0-∞ for single-dose, AUC0-24 for once daily. † Changes in doravirine pharmacokinetic values are not clinically relevant. ‡ Doravirine 100 mg BID resulted in similar pharmacokinetic values when compared to 100 mg QD without rifabutin. § A single doravirine 50 mg dose (0.5 times the recommended approved dose) was administered. ¶ The first day following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. # 14 days following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD.
Azole Antifungal Agents
ketoconazole †	400 mg QD	10	3.06 (2.85, 3.29)	1.25 (1.05, 1.49)	2.75 (2.54, 2.98)
Antimycobacterials
rifampin	600 mg QD	10	0.12 (0.10, 0.15)	0.43 (0.35, 0.52)	0.03 (0.02, 0.04)
rifabutin	300 mg QD	12	0.50 (0.45, 0.55)	0.99 (0.85, 1.15)	0.32 (0.28, 0.35)
	300 mg QD ‡	15	1.03 (0.94, 1.14)	0.97 (0.87, 1.08)	0.98 (0.88, 1.10)
HIV Antiviral Agents
ritonavir †, §	100 mg BID	8	3.54 (3.04, 4.11)	1.31 (1.17, 1.46)	2.91 (2.33, 3.62)
efavirenz	600 mg QD ¶	17	0.38 (0.33, 0.45)	0.65 (0.58, 0.73)	0.15 (0.10, 0.23)
	600 mg QD #	17	0.68 (0.58, 0.80)	0.86 (0.77, 0.97)	0.50 (0.39, 0.64)

Based on drug interaction studies conducted with doravirine, no clinically significant drug interactions have been observed following the co-administration of doravirine and the following drugs: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, ritonavir, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam.

Lamivudine:

Trimethoprim/Sulfamethoxazole: Co-administration of TMP/SMX with lamivudine resulted in an increase of 43% ±23% (mean ±SD) in lamivudine AUC∞, a decrease of 29% ±13% in lamivudine oral clearance, and a decrease of 30% ±36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by co-administration with lamivudine.

Sorbitol (Excipient): Co-administration of lamivudine with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol resulted in dose-dependent decreases of 14%, 32%, and 36% in the AUC∞; and 28%, 52%, and 55% in the Cmax of lamivudine, respectively.

TDF:

No clinically significant changes in exposure were observed for tenofovir when co-administered with tacrolimus or entecavir.

No clinically significant changes in exposure were observed for the following drugs when co-administered with tenofovir: tacrolimus, entecavir, methadone, or ethinyl estradiol/norgestimate.