12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

SUNLENCA is an HIV-1 antiretroviral agent [see Microbiology (12.4)].

12.2 Pharmacodynamics

Exposure-Response

In CAPELLA, oral loading doses (600 mg on Day 1 and Day 2, 300 mg on Day 8) followed by subcutaneous doses (927 mg every 6 months starting on Day 15) of SUNLENCA in heavily treatment-experienced participants with multiclass resistant HIV-1, efficacy outcomes (change in plasma HIV-1 RNA from Day 1 to Day 14, and percentage of participants with HIV-1 RNA less than 50 copies/mL at Week 26) were similar across the range of observed lenacapavir exposures.

Cardiac Electrophysiology

At supratherapeutic exposures of lenacapavir (9-fold higher than the therapeutic exposures of SUNLENCA), SUNLENCA does not prolong the QTcF interval to any clinically relevant extent.

12.3 Pharmacokinetics

The pharmacokinetic (PK) properties of lenacapavir are provided in Table 6 and Table 7. The estimated lenacapavir exposures are comparable between the two recommended dosing regimens.

Table 6 Pharmacokinetic Properties of Lenacapavir
		Oral	Subcutaneous
* Values reflect absolute bioavailability following subcutaneous administration of the 927 mg dose. † Values reflect administration of lenacapavir with or without food. ‡ Due to slow release from the site of subcutaneous administration, the absorption profile of subcutaneously administered lenacapavir is complex. § Values refer to geometric mean ratio [low-fat meal/fasting] in PK parameters and (90% confidence interval). Low fat meal is approximately 400 kcal, 25% fat. ¶ Values refer to geometric mean ratio [high-fat meal/fasting] in PK parameters and (90% confidence interval). High fat meal is approximately 1000 kcal, 50% fat. # Values reflect the blood-to-plasma ratio of lenacapavir following a single dose intravenous administration of [14C] lenacapavir through 336 hours postdose. Þ Dosing in mass balance studies: single dose intravenous administration of [14C] lenacapair to participants without HIV-1. ß Metabolized via oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation; primarily via CYP3A and UGT1A1 and no single circulating metabolite accounted for >10% of plasma drug-related exposure.
Absorption
% Absolute bioavailability		6 to 10	100 *
Tmax †		4 hours	77 to 84 days ‡
Effect of Food
Effect of low-fat meal (relative to fasting) §	AUCinf ratio	98.6 (58.2,167.2)	-
Effect of low-fat meal (relative to fasting) §	Cmax ratio	115.8 (55.4, 242.1)	-
Effect of high-fat meal (relative to fasting) ¶	AUCinf ratio	115.2 (72.0, 184.5)	-
Effect of high-fat meal (relative to fasting) ¶	Cmax ratio	145.2 (77.9, 270.5)	-
Distribution
Apparent volume of distribution (Vd/F, L)		19240	9500 to 11700
% bound to human plasma proteins		>98.5
Blood-to-plasma ratio		0.5 to 0.7 #
Elimination
t1/2		10 to 12 days	8 to 12 weeks
Clearance (mean apparent clearance, L/h)		55	4.2
% of dose of unchanged drug in plasma Þ		69
Metabolism
Metabolic pathway(s)		CYP3A (minor) UGT1A1 (minor)
Excretion
Major routes of elimination		Excretion of unchanged drug into feces ß
% of dose excreted in urine Þ		<1
% of dose excreted in feces (% unchanged) ß		76 (33)

Table 7 Lenacapavir Exposures Following Oral and Subcutaneous Administration of SUNLENCA in Heavily Treatment Experienced Participants with HIV
Parameter Mean (%CV)	Recommended Dosing Regimen, Option 1 *	Recommended Dosing Regimen, Option 2 *
	Day 1: 600 mg (oral) + 927 mg (SC) Day 2: 600 mg (oral)	Days 1 and 2: 600 mg (oral), Day 8: 300 mg (oral), Day 15: 927 mg (SC)
	Day 1 to end of Month 6	Days 1 to 15	Day 15 to end of Month 6
CV = coefficient of variation; NA = not applicable; SC = subcutaneous
* Predicted exposures utilizing population PK analysis.
Cmax (ng/mL)	101.4 (53.1)	88.0 (72.4)	86.5 (51.7)
AUCtau (h∙ng/mL)	242266 (46.0)	19496 (72.6)	239163 (47.2)
Ctrough (ng/mL)	32.5 (57.2)	46.9 (72.3)	32.5 (57.5)

Lenacapavir exposures after subcutaneous administration were similar between heavily treatment experienced participants with HIV-1 and participants without HIV-1 based on population pharmacokinetics analysis. Lenacapavir exposures (AUCtau, Cmax and Ctrough) after oral administration were 28% to 43% higher in participants with HIV-1 who were heavily treatment experienced, compared to participants without HIV-1 based on population PK analysis. These differences were not considered clinically relevant.

Specific Populations

There were no clinically significant differences in the pharmacokinetics of lenacapavir based on age (18 to 78 years), sex, ethnicity (hispanic or non-hispanic), race (white, black, asian or other), body weight (41.4 to 164 kg), severe renal impairment (creatinine clearance of 15 to less than 30 mL per minute, estimated by Cockroft-Gault method), or moderate hepatic impairment (Child-Pugh Class B). The effect of end-stage renal disease (including dialysis), or severe hepatic impairment (Child-Pugh Class C), on the pharmacokinetics of lenacapavir is unknown. As lenacapavir is greater than 98.5% protein bound, dialysis is not expected to alter exposures of lenacapavir [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Clinical drug-drug interaction study indicated that lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1. Table 8 summarizes the pharmacokinetic effects of other drugs on lenacapavir.

Lenacapavir is a moderate inhibitor of CYP3A. Lenacapavir is an inhibitor of P-gp and BCRP but does not inhibit OATP. Table 9 summarizes the pharmacokinetic effects of lenacapavir on other drugs.

Table 8 Effect of Other Drugs on Lenacapavir *,†
Coadministered Drug	Dose of Coadministered Drug (mg)	Mean Ratio of Lenacapavir Pharmacokinetic Parameters (90% CI); No effect = 1.00
Coadministered Drug	Dose of Coadministered Drug (mg)	Cmax	AUC
* Single dose of lenacapavir 300 mg administered orally. † All interaction studies conducted in participants without HIV-1. ‡ 400 mg loading dose twice daily for a day, followed by 200 mg maintenance dose twice daily.
Cobicistat (fed) (Inhibitor of CYP3A [strong] and P-gp)	150 once daily	2.10 (1.62, 2.72)	2.28 (1.75, 2.96)
Darunavir / cobicistat (fed) (Inhibitor of CYP3A [strong] and inhibitor and inducer of P-gp)	800/150 once daily	2.30 (1.79, 2.95)	1.94 (1.50, 2.52)
Voriconazole (fasted) (Inhibitor of CYP3A [strong])	400 twice daily, 200 twice daily ‡	1.09 (0.81, 1.47)	1.41 (1.10, 1.81)
Atazanavir / cobicistat (fed) (Inhibitor of CYP3A [strong] and UGT1A1 and P-gp)	300/150 once daily	6.60 (4.99, 8.73)	4.21 (3.19, 5.57)
Rifampin (fasted) (Inducer of CYP3A [strong] and P-gp and UGT)	600 once daily	0.45 (0.34, 0.60)	0.16 (0.12, 0.20)
Efavirenz (fasted) (Inducer of CYP3A [moderate] and P-gp)	600 once daily	0.64 (0.45, 0.92)	0.44 (0.32, 0.59)
Famotidine (2 hours before, fasted)	40 once daily	1.01 (0.75, 1.34)	1.28 (1.00, 1.63)

Table 9 Effect of Lenacapavir on Other Drugs *,†
Coadministered Drug	Dose of Coadministered Drug (mg)	Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI) ‡; No effect = 1.00
Coadministered Drug	Dose of Coadministered Drug (mg)	Cmax	AUC
* All interaction studies conducted in participants without HIV-1. † Following 600 mg twice daily for 2 days, single 600 mg doses of lenacapavir were administered with each coadministered drug, resulting in lenacapavir exposures similar to or higher than those at the recommended dosage regimen. ‡ All No Effect Boundaries are 70% to 143%. § Tenofovir alafenamide is converted to tenofovir in vivo. ¶ Major active metabolite of midazolam.
Tenofovir alafenamide (fed) (substrate of P-gp)	25 single dose	1.24 (0.98, 1.58)	1.32 (1.09, 1.59)
Tenofovir § (substrate of P-gp)		1.23 (1.05, 1.44)	1.47 (1.27, 1.71)
Pitavastatin (simultaneous administration, fed) (substrate of OATP)	2 single dose	1.00 (0.84, 1.19)	1.11 (1.00, 1.25)
Pitavastatin (3 days after lenacapavir, fed) (substrate of OATP)	2 single dose	0.85 (0.69, 1.05)	0.96 (0.87, 1.07)
Rosuvastatin (fed) (substrate of BCRP and OATP)	5 single dose	1.57 (1.38, 1.80)	1.31 (1.19, 1.43)
Midazolam (simultaneous administration, fed) (substrate of CYP3A)	2.5 single dose	1.94 (1.81, 2.08)	3.59 (3.30, 3.91)
1-hydroxymidazolam ¶ (substrate of CYP3A)		0.54 (0.50, 0.59)	0.76 (0.72, 0.80)
Midazolam (1 day after lenacapavir, fed) (substrate of CYP3A)	2.5 single dose	2.16 (2.02, 2.30)	4.08 (3.77, 4.41)
1-hydroxymidazolam ¶ (substrate of CYP3A)		0.52 (0.48, 0.57)	0.84 (0.80, 0.88)

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Lenacapavir is not a substrate, inducer, or inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Lenacapavir is not an inducer of CYP3A4.

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Lenacapavir is not an inhibitor of UGT1A1.

Transporter Systems: Lenacapavir is not an inhibitor of organic anion transporter 1 (OAT1), OAT3, organic cation transporter (OCT)1, OCT2, multidrug and toxin extrusion transporter (MATE) 1, or MATE 2-K. Lenacapavir is not a substrate of BCRP, OATP1B1, or OATP1B3.

12.4 Microbiology

Mechanism of Action

Lenacapavir is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to the interface between capsid protein (p24) subunits in hexamers. Surface plasmon resonance sensorgrams showed dose-dependent and saturable binding of lenacapavir to cross-linked wild-type capsid hexamer with an equilibrium binding constant (KD) of 1.4 nM. Lenacapavir inhibits HIV-1 replication by interfering with multiple essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of capsid protein subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids).

Antiviral Activity in Cell Culture

Lenacapavir has antiviral activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2). The antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed in T-lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes with EC50 values ranging from 30 to 190 pM. Lenacapavir displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes A, A1, AE, AG, B, BF, C, D, E, F, G with EC50 values ranging from 20 and 160 pM. The median EC50 value for subtype B isolates (n=8) was 40 pM. Lenacapavir was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1.

In a study of lenacapavir in combination with representatives from the major classes of anti-retroviral agents (INSTIs, NNRTIs, NRTIs, and PIs), no antagonism of antiviral activity was observed.

Resistance

In Cell Culture

HIV-1 variants with reduced susceptibility to lenacapavir have been selected in cell culture. Resistance selections with lenacapavir identified 7 substitutions in capsid: L56I, M66I, Q67H, K70N, N74D/S, and T107N singly or in dual combination that conferred 4- to >3,226-fold reduced phenotypic susceptibility to lenacapavir relative to wild-type (WT) virus. The M66I substitution alone or in combination conferred >3,226-fold decreased susceptibility to lenacapavir in a single-cycle infectivity assay; substitutions Q67H and T107N, conferred 4- to 6.3-fold decreased susceptibility; K70N, N74D and Q67H/N74S conferred 22- to 32-fold decreased susceptibility; and L56I conferred 239-fold decreased susceptibility.

In Clinical Trials

In CAPELLA, 31% (22/72) of heavily treatment-experienced participants met the criteria for resistance analyses through Week 52 (HIV-1 RNA ≥ 50 copies/mL at confirmed virologic failure [suboptimal virologic response at Week 4, virologic rebound, or viremia at last visit]) and were analyzed for lenacapavir resistance-associated substitution emergence. Lenacapavir resistance-associated capsid substitutions were found in 41% (n=9) of participants with confirmed virologic failure who had post-baseline capsid genotypic resistance data (n=22). The M66I capsid substitution was observed in 27% (6/22) of participants, alone or in combination with other lenacapavir resistance-associated capsid substitutions including Q67Q/H, Q67Q/H/K/N, K70K/R, K70N/S, N74D, N74N/H, A105T, and T107A. The other 3 participants with virologic failure had emergent lenacapavir resistance-associated capsid substitutions Q67K+K70H, Q67H+K70R+T107S, and Q67Q/H.

Phenotypic analyses of the confirmed virologic failure isolates with emergent lenacapavir resistance-associated substitutions showed 6- to >1428-fold decreases in lenacapavir susceptibility when compared to WT.

Among the 9 participants with virologic failure who developed lenacapavir resistance-associated substitutions in capsid, 4 received SUNLENCA in combination with a background regimen with no fully active antiretrovirals based on the baseline genotypic and/or phenotypic resistance. Therefore, given the risk of developing resistance in situations of functional monotherapy, careful consideration should be given to having active drugs in addition to SUNLENCA in the treatment regimen.

Four participants with virologic failure had emergent resistance substitutions to components of the optimized background regimen (OBR): emergent NRTI substitution M184I/V and NNRTI substitution K103N/Y with emtricitabine and doravirine plus atazanavir, bictegravir, and tenofovir alafenamide in OBR; emergent NNRTI substitution V106M from a mixture at baseline (in addition to lenacapavir resistance-associated substitutions M66I + T107A) with doravirine plus emtricitabine and ibalizumab in OBR; emergent NRTI substitutions K65R and S68N from mixtures at baseline (in addition to lenacapavir resistance-associated substitution M66I) with tenofovir alafenamide, plus emtricitabine, dolutegravir, darunavir/cobicistat, and rilpivirine in OBR; and emergent NRTI substitution K65K/R with tenofovir disoproxil fumarate plus darunavir/cobicistat, dolutegravir, and emtricitabine in OBR.

Oral Maintenance for Missed Injections

Of the 57 participants who received oral maintenance, 9 participants (5 participants in Cohort 1 and 4 participants in Cohort 2) met the criteria for resistance analysis. Six of these 9 participants had emergent lenacapavir resistance substitutions in capsid (Q67H [n=4], K70R or N [n=2], N74D or K [n=2], T107N [n=1]) with 4.5- to 393-fold decreased lenacapavir susceptibility. In addition, 2 participants had emergent resistance substitutions to darunavir in their optimized background regimen.

Lenacapavir Resistance with Suboptimal Adherence to Other Antiretroviral Drugs in the Regimen

The development of lenacapavir-associated capsid resistance substitutions in 6 participants during the oral maintenance period was likely due to suboptimal adherence to the optimized background oral regimens that included dolutegravir and/or darunavir. After developing lenacapavir resistance, 5 of the 6 participants achieved HIV-1 RNA resuppression (HIV-1 RNA < 50 copies/mL) while maintaining SUNLENCA treatment. With the emergence of lenacapavir resistance substitutions and decreased susceptibility to lenacapavir, it is unclear how much antiviral activity lenacapavir is contributing to the resuppression of HIV-1 RNA in these 5 participants.

Thus, adherence to other antiretroviral drugs in the regimen should be optimized while the patient is receiving SUNLENCA. During SUNLENCA treatment, if suboptimal adherence to the oral antiretroviral regimen occurs with concurrent HIV-1 RNA viral load increases (i.e., virologic failure), lenacapavir resistance should be assessed, and if detected, consideration should be given to discontinuing SUNLENCA treatment [see Dosage and Administration (2.1), Warnings and Precautions (5.2)].

Cross-Resistance

The antiviral activity in cell culture of lenacapavir was determined against a broad spectrum of HIV-1 site-directed mutants and patient-derived HIV-1 isolates with resistance to the four main classes of anti-retroviral agents (INSTI, NNRTI, NRTI, and PI; n=58), as well as to viruses resistant to the gp120-directed attachment inhibitor fostemsavir, the CD4+-directed post-attachment inhibitor ibalizumab, the CCR5 co-receptor antagonist maraviroc, and the gp41 fusion inhibitor enfuvirtide (n=42). These data indicated that lenacapavir remained fully active against all variants tested, thereby demonstrating a non-overlapping resistance profile. In addition, the antiviral activity of lenacapavir in patient isolates was unaffected by the presence of naturally occurring Gag polymorphisms and substitutions at protease cleavage sites.