Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir

Abstract

The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT02356562 and NCT02292719.)

INTRODUCTION

A combination of three direct-acting antivirals (DAA) (3D regimen) with or without ribavirin has been approved by the U.S. Food and Drug Administration and the European Medicines Agency, among other regulatory agencies, for the treatment of patients with chronic HCV genotype 1 (GT1) infection, including those with compensated cirrhosis (1, 2). The 3D regimen consists of paritaprevir, a nonstructural 3/4A (NS3/4A) protease inhibitor identified as a lead compound by AbbVie and Enanta, coadministered with ritonavir (r), administered once daily (paritaprevir-r); ombitasvir, a NS5A inhibitor, administered once daily; and dasabuvir, a nonnucleoside NS5B RNA polymerase inhibitor, administered twice daily. The two-DAA combination regimen (2D regimen) consisting of paritaprevir-r, ombitasvir, and ribavirin has shown potent antiviral activity in vitro against HCV GT1a, -1b, -2a, -2b, -3A, -4a, and -6a. Thus, several clinical studies have evaluated the 2D regimen with or without ribavirin in patients with HCV genotype 1b, 2, 3, and 4 infections (3, 4, 5, 6). The 2D regimen with ribavirin is approved by the European Medicines Agency for the treatment of patients with chronic HCV GT4 infection, including those with compensated cirrhosis (2).

Sofosbuvir, a nucleotide analog NS5B polymerase inhibitor, is approved for the treatment of patients with chronic HCV GT1, -2, -3, or -4 infection (7, 8, 9). After oral administration, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007. Sofosbuvir is a substrate of the drug transporters P glycoprotein (P-gp) and breast cancer resistance protein (BCRP), while GS-331007 is not a substrate of these transporters (9). Ombitasvir, paritaprevir, ritonavir, and dasabuvir are also P-gp substrates, and all except for ritonavir are also BCRP substrates (10). In addition, paritaprevir, ritonavir, and dasabuvir are inhibitors of P-gp and BCRP. Based on their transporter affinity profiles, the 2D and 3D regimens have the potential to increase plasma concentrations of sofosbuvir but not GS-331007. The combination of 3D or 2D and SOF is currently being evaluated in HCV-infected subjects (www.clinicaltrials.gov, entries NCT02356562 and NCT02292719). Combining the 2D or 3D regimen with SOF, which has a distinct mechanism of action (termination of the nascent RNA chain), may increase the antiviral activity of the regimen, potentially increasing response rates and/or allowing a shorter treatment duration. This study was designed to assess the pharmacokinetics, safety, and tolerability of sofosbuvir in combination with the 3D or 2D regimen in healthy volunteers and inform the dose selection and design of the study in HCV-infected subjects.

MATERIALS AND METHODS

The bidirectional drug-drug interactions between sofosbuvir and 3D or 2D were evaluated in a phase 1, single-center, randomized, multiple-dose, nonfasting, open-label study in healthy male and female adults. Written informed consent was obtained from all subjects, and the institutional review board of the study site (AbbVie Clinical Research Unit, Grayslake, IL) approved the protocol.

A steady-state design was selected to address any potential inhibition effects from the 3D or 2D regimen and to simulate clinically relevant exposures. A sample size of 8 per cohort was selected to make allowances for premature discontinuations. Complete data from 7 subjects would provide at least 82% power for the test on paritaprevir AUC if the ratio of the central values is 2. The power calculations were performed using logarithmic transformation. The calculation assumed the error term variance of 0.1409 for the natural logarithm of paritaprevir AUC. This value was selected based on previous studies, and the variability of other drugs evaluated was expected to be smaller than that of paritaprevir.

Thirty-two adult male and female subjects in general good health were selected to participate in the study according to selection criteria. Sixteen subjects were enrolled in arm 1 (ombitasvir-paritaprevir-r, 25/150/100 mg daily [QD], with dasabuvir, 250 mg twice daily [BID], and sofosbuvir, 400 mg QD), referred to as the 3D arm, and 16 subjects were enrolled in arm 2 (ombitasvir-paritaprevir-r, 25/150/100 mg QD, plus sofosbuvir, 400 mg QD), referred to as the 2D arm. Within each arm, subjects were randomly assigned in a 1:1 ratio to cohort 1 or cohort 2 as illustrated in Fig. 1. In cohort 1, 8 subjects received 3D (arm 1) or 2D (arm 2) on study days 1 through 14. On study days 15 through 21, sofosbuvir 400 mg QD was administered along with 3D (arm 1) or 2D (arm 2). In cohort 2, 8 subjects received 400 mg sofosbuvir QD on study days 1 through 7, and on study days 8 through 21, 400 mg sofosbuvir was administered QD along with 3D (arm 1) or 2D (arm 2). All study medications in both arms were administered with a standardized meal, providing approximately 40% of the daily calories from fat and up to 45% of the daily calories from carbohydrates (approximately 2,200 cal/day).

FIG 1.

Study design for the 3D arm (arm 1) and the 2D arm (arm 2).

Subject eligibility was determined by medical history, physical examination, vital signs, electrocardiogram, and laboratory screening tests. Healthy volunteers of either sex between the ages of 18 and 55 years (inclusive) at the time of signing the informed consent with a body mass index (BMI) within the range of 18 to <30 kg/m² were eligible to participate in the study. Female subjects were required to be of nonchildbearing potential or to practice birth control to be eligible for the study. Male subjects with female partners of childbearing potential had to use specified contraception methods. Pregnant and lactating females were not eligible.

Subjects were ineligible if they had significant sensitivity to any drug, a positive prestudy hepatitis A immunoglobulin M test, a positive hepatitis B surface antigen test, a positive hepatitis C virus antibody test, or a positive test for human immunodeficiency virus antibody. Use of prescription or nonprescription drugs, including vitamins or herbal and dietary supplements was precluded within 2 weeks prior to the first dose of study medication. Subjects were ineligible if they used known inhibitors or inducers of CYP3A, CYP2C8, uridine 5'-diphospho-glucuronosyltransferase (UGT), organic anion transporter 1 (OAT1), OAT3, or organic anion transporting polypeptide 1B1 (OATP1B1) within 1 month prior to study drug administration. Subjects could not have consumed grapefruit, star fruit, Seville oranges, products containing any of these ingredients, and/or quinine or tonic water within the 72-hour period prior to study drug administration. Subjects had screening visits within 28 days prior to the first dose of the study drug and a follow-up visit approximately 10 days after the last dose of the study drug.

Bioanalytical methods. (i) Ombitasvir, paritaprevir, ritonavir, and dasabuvir.

Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir were determined using a validated protein precipitation and on-line solid-phase extraction method with liquid chromatography and tandem mass spectrometric detection (LC-MS/MS). The lower limits of quantitation (LLOQ) for paritaprevir, ritonavir, ombitasvir, and dasabuvir were 0.610 ng/ml (interrun accuracy [bias], −4.6% to 5.2%; interrun precision [coefficient of variation {CV}], 1.1% to 3.4%), 4.98 ng/ml (bias, −4.5% to 3.6%; CV, 0.8% to 3.8%), 0.451 ng/ml (bias, −4.0% to 4.0%; CV, 0.8% to 4.7%), and 4.84 ng/ml (bias, −2.9% to −5.4%; CV, 1.4% to 4.9%), respectively.

Plasma concentrations of sofosbuvir and GS-331007 were determined using a validated extraction and high-performance liquid chromatography method with tandem mass spectrometric detection. The LLOQ for sofosbuvir and GS-331007 were 5 ng/ml (interrun accuracy [bias], 0.0% to 8.5%; interrun precision [CV], 2.8% to 4.4%) and 10 ng/ml (bias, 3.0%; CV, 10.2%).

(ii) Pharmacokinetic assessment and analysis.

In cohort 1 of the 3D and 2D arms, blood samples for determination of ombitasvir, paritaprevir, ritonavir, and dasabuvir plasma concentrations were collected prior to morning dosing (0 h) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after the morning dosing on study days 14 and 21. Samples were also collected 36 and 48 h after the morning dose on study day 21. Blood samples for determination of sofosbuvir and GS-331007 plasma concentrations were collected prior to morning dosing (0 h) and at 0.5 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after morning dosing on study day 21.

In cohort 2 of the 3D and 2D arms, blood samples for determination of sofosbuvir and GS-331007 plasma concentrations were collected prior to morning dosing (0 h) and at 0.5 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after morning dosing on study days 7 and 21. Samples were also collected 36 and 48 h after the morning dose on study day 21. Blood samples for determination of ombitasvir, paritaprevir, ritonavir, and dasabuvir plasma concentrations were collected prior to morning dosing (0 h) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after the morning dosing on study day 21.

Pharmacokinetic parameters for ombitasvir, paritaprevir, ritonavir, dasabuvir, sofosbuvir, and GS-331007 were estimated by noncompartmental methods. The pharmacokinetic parameters assessed were maximum plasma concentration (C_max), time to C_max (T_max), trough concentration (C_trough) (concentration at 24 h [C₂₄] for QD regimens and C₁₂ for BID regimens), area under the plasma concentration-time curve (AUC; AUC₂₄ and AUC₁₂ for study drugs administered QD and BID, respectively), and terminal-phase half-life (t_1/2).

(iii) Statistical analysis.

Statistical analyses were conducted using SAS version 9.2 (SAS Institute, Inc., Cary, NC). Effects of the 2D and 3D regimens on sofosbuvir and GS-331007 exposures and vice versa were estimated by analyzing natural log transformed C_max, AUC, and C_trough (C₂₄ for QD regimens and C₁₂ for BID regimens) values under a repeated-measures analysis framework. Central value ratios and 90% confidence intervals (CIs) for C_max, AUC, and C_trough were calculated to quantify the magnitude of drug interactions.

RESULTS

Demographics.

Sixteen subjects were enrolled in the 3D arm, and 13 completed both treatments. Two subjects in cohort 1 discontinued prematurely, one on study day 1 due to an inability to swallow pills and one on study day 9 because of disruptive behavior. One subject in cohort 2 discontinued prematurely due to a soft tissue infection on the face. Sixteen subjects were enrolled in the 2D arm, and 15 completed both treatments. One subject in cohort 2 discontinued prematurely on study day 4 due to a family emergency. Baseline patient demographics are summarized in Table 1.

TABLE 1.

Demographic summary for all subjects

Characteristic	Value (n = 32)	Range
Age (yr)	37.1 ± 9.92a	22–51
Weight (kg)	77.5 ± 11.1a	61–99
Height (cm)	173 ± 7.55a	159–185
Sex	25 males (78.1%), 7 females (21.9%)
Race	9 white (28.1%), 21 black (65.6%), 2 Asian (6.3%)

^aMean ± standard deviation.

Safety.

Coadministration of 3D or 2D regimens with sofosbuvir was generally well tolerated by 28 healthy subjects for 7 to 14 days of coadministration. No new or unexpected safety findings were observed. No serious adverse events were reported. No adverse events (AE) occurred among 13 subjects during the period when the 3D regimen was coadministered with sofosbuvir, while 9 AEs (3 episodes of fatigue and one each of lymphadenopathy, diarrhea, pyrexia, furuncle, decreased appetite, and headache) occurred in 5 of 15 subjects during the period when the 2D regimen was coadministered with sofosbuvir. Only the 3 episodes of fatigue and the incidence of decreased appetite were considered possibly related to the DAAs during these periods. AEs occurring during administration of 3D, 2D, or sofosbuvir alone were all mild and included single events of abdominal pain, constipation, headache, and trauma related to phlebotomy; no pattern was apparent. One AE occurring during the study led to premature discontinuation from study drug administration, a soft tissue infection of the face occurring while a subject was receiving sofosbuvir alone. No clinically significant hematology, serum chemistry, or urine analysis values were observed.

Pharmacokinetics.

Pharmacokinetic parameters for the analytes are summarized in Tables 2 and 3 for the 3D arm and Tables 4 and 5 for the 2D arm. Concentration time profiles for sofosbuvir and GS-331007 are shown in Fig. 2.

TABLE 2.

Pharmacokinetic parameters and ratios of central values for the 3D arm (n = 6)

Drug and pharmacokinetic parameter	Geometric mean (CV [%]) on study day:		Ratio of central valuesa
	14b	21c	Point estimate	90% confidence interval
Ombitasvir
Cmax (ng/ml)	126 (21)	117 (29)	0.93	0.84–1.03
AUC24 (ng · h/ml)	1,290 (22)	1,200 (27)	0.93	0.87–0.99
C24 (ng/ml)	25.4 (26)	23.3 (29)	0.92	0.88–0.96
Tmax (h)d	5.0 (4.0–6.0)	5.0 (4.0–6.0)
t1/2 (h)e	11.7 (2.7)	18.6 (2.6)
Paritaprevir
Cmax (ng/ml)	758 (65)	614 (73)	0.81	0.65–1.01
AUC24 (ng · h/ml)	3,390 (55)	2,860 (57)	0.85	0.71–1.01
C24 (ng/ml)	8.1 (50)	6.6 (41)	0.82	0.67–1.01
Tmax (h)d	4.5 (4.0–6.0)	4.0 (3.0–5.0)
t1/2 (h)e	4.4 (0.9)	4.5 (0.2)
Ritonavir
Cmax (ng/ml)	1,630 (55)	1,440 (64)	0.88	0.78–1.00
AUC24 (ng · h/ml)	8,800 (42)	7,840 (55)	0.89	0.80–0.99
C24 (ng/ml)	26.7 (55)	23.0 (49)	0.86	0.79–0.94
Tmax (h)d	4.5 (3.0–6.0)	4.0 (3.0–5.0)
t1/2 (h)e	4.3 (0.7)	4.6 (0.8)
Dasabuvir
Cmax (ng/ml)	984 (60)	1,080 (51)	1.09	0.98–1.22
AUC12 (ng · h/ml)	6,660 (47)	6,810 (46)	1.02	0.95–1.10
C12 (ng/ml)	293 (47)	248 (48)	0.85	0.76–0.95
Tmax (h)d	4.0 (3.0–5.0)	3.0 (3.0–5.0)
t1/2 (h)e	11.4 (5.3)	5.7 (0.5)

^aDay 21/day 14.

^bArm 1, cohort 1, study day 14: 25/150/100 mg ombitasvir–paritaprevir–r QD plus 250 mg dasabuvir BID.

^cArm 1, cohort 1 and cohort 2, study day 21: 25/150/100 mg ombitasvir–paritaprevir–r QD plus 250 mg dasabuvir BID plus 400 mg QD sofosbuvir.

^dMedian (range).

^eHarmonic mean (pseudo-standard deviation).

TABLE 3.

Pharmacokinetic parameters and ratios of central values for sofosbuvir and GS-331007 in the 3D arm (n = 7)

Drug and pharmacokinetic parameter	Geometric mean (CV [%]) on study day:		Central valuea
	7b	21c	Point estimate	90% confidence interval
Sofosbuvir
Cmax (ng/ml)	658 (37)	1,060 (38)	1.61	1.38–1.88
AUC24 (ng · h/ml)	1,010 (22)	2,150 (26)	2.12	1.91–2.37
C24 (ng/ml)	NAf	NA	NA	NA
Tmax (h)d	1.0 (1.0–2.0)	2.0 (0.5–2.0)
t1/2 (h)e	0.5 (0.1)	0.6 (0.1)
GS-331007
Cmax (ng/ml)	1,650 (22)	1,690 (17)	1.02	0.90–1.16
AUC24 (ng · h/ml)	15,800 (25)	20,100 (14)	1.27	1.14–1.42
C24 (ng/ml)	282 (29)	499 (16)	1.77	1.52–2.07
Tmax (h)d	3.0 (2.0–5.0)	3.0 (2.0–5.0)

^aDay 21/day 7.

^bArm 1, cohort 2, study day 7: 400 mg sofosbuvir QD.

^cArm 1, cohort 2, study day 21: 25/150/100 mg ombitasvir–paritaprevir–r QD plus 250 mg dasabuvir BID plus 400 mg sofosbuvir QD.

^dMedian (range).

^eHarmonic mean (pseudo-standard deviation).

^fNA, not applicable.

TABLE 4.

Pharmacokinetic parameters and ratios of central values for the 2D arm (n = 8)

Drug and pharmacokinetic parameter	Geometric mean (CV [%]) on study day:		Ratio of central valuesa
	14b	21c	Point estimate	90% confidence interval
Ombitasvir
Cmax (ng/ml)	104 (30)	100 (35)	0.96	0.89–1.04
AUC24 (ng · h/ml)	1,110 (28)	1,040 (35)	0.93	0.87–1.00
C24 (ng/ml)	20.0 (37)	18.0 (37)	0.90	0.84–0.96
Tmax (h)d	5.0 (3.0–5.0)	5.0 (3.0–5.0)
t1/2 (h)e	10.8 (2.0)	18.7 (6.7)
Paritaprevir
Cmax (ng/ml)	1,670 (96)	1,500 (106)	0.90	0.63–1.28
AUC24 (ng · h/ml)	7,120 (90)	6,440 (125)	0.91	0.62–1.31
C24 (ng/ml)	14.3 (77)	14.2 (93)	0.99	0.66–1.50
Tmax (h)d	3.5 (2.0–5.0)	3.0 (2.0–6.0)
t1/2 (h)e	3.7 (0.6)	5.3 (0.7)
Ritonavir
Cmax (ng/ml)	1,810 (25)	1,790 (19)	0.99	0.91–1.07
AUC24 (ng · h/ml)	11,000 (19)	10,400 (23)	0.94	0.88–1.00
C24 (ng/ml)	31.6 (45)	29.4 (49)	0.93	0.84–1.03
Tmax (h)d	3.0 (2.0–5.0)	3.0 (2.0–4.0)
t1/2 (h)e	3.4 (0.5)	4.0 (1.2)

^aDay 21/day 14.

^bArm 2, cohort 1, study day 14: 25/150/100 mg ombitasvir–paritaprevir–r QD.

^cArm 2, cohort 1, study day 21: 25/150/100 mg ombitasvir–paritaprevir–r QD plus 400 mg sofosbuvir QD.

^dMedian (range).

^eHarmonic mean (pseudo-standard deviation).

TABLE 5.

Pharmacokinetic parameters and ratios of central values for sofosbuvir and GS-331007 in the 2D arm (n = 7)

Drug and pharmacokinetic parameter	Geometric mean (CV) on study day:		Ratio of central valuesa
	7b	21c	Point estimate	90% confidence interval
Sofosbuvir
Cmax (ng/ml)	706 (41)	1,160 (45)	1.64	0.99–2.71
AUC24 (ng · h/ml)	1,090 (40)	2,100 (42)	1.93	1.41–2.64
C24 (ng/ml)	NAf	NA	NA	NA
Tmax (h)d	2.0 (0.5–3.0)	1.0 (0.6–3.0)
t1/2 (h)e	0.5 (0.08)	0.5 (0.06)
GS-331007
Cmax (ng/ml)	1,290 (34)	1,500 (28)	1.16	1.04–1.30
AUC24 (ng · h/ml)	13,000 (28)	17,200 (22)	1.32	1.25–1.39
C24 (ng/ml)	258 (38)	441 (30)	1.71	1.49–1.96
Tmax (h)d	3.0 (3.0–5.0)	3.0 (3.0–6.0)

^aDay 21/day 7.

^bArm 2, cohort 2, study day 7: 400 mg sofosbuvir QD.

^cArm 2, cohort 2, study day 21: 25/150/100 mg ombitasvir–paritaprevir–r QD plus 400 mg sofosbuvir QD.

^dMedian (range).

^eHarmonic mean (pseudo-standard deviation).

^fNA, not applicable.

FIG 2.

Mean plasma concentration-time profiles of sofosbuvir and GS-331007 with (day 21) and without (day 7) the 3D (arm 1) and 2D (arm 2) regimen.

3D with sofosbuvir.

When the 3D regimen was coadministered with sofosbuvir, steady-state exposures of paritaprevir, ritonavir, ombitasvir, and dasabuvir were minimally affected (<20% change). Sofosbuvir C_max and AUC increased 61% to 112%, respectively, while T_max (∼1 h) did not differ. Sofosbuvir has a relatively short half-life of 0.5 h, which did not change in the presence of the 3D regimen. The GS-331007 AUC increased 27% in the presence of the 3D regimen, while the GS-331007 C_trough was 77% higher.

2D with sofosbuvir.

When the 2D regimen was coadministered with sofosbuvir, steady-state exposures of paritaprevir, ritonavir, and ombitasvir were minimally affected (<20% change). Sofosbuvir C_max and AUC increased 64% and 93%, respectively, while T_max (∼1 h) and t_1/2 (∼0.5 h) did not change. The GS-331007 AUC increased 32% in the presence of the 2D regimen, and the GS-331007 C_trough was 71% higher.

DISCUSSION

All oral, interferon-free DAA regimens have improved the efficacy of HCV therapy and reduced the duration of treatment to 12 weeks or less for most patients. Various HCV genotypes, however, remain difficult to treat, and combinations of highly active DAAs may enhance efficacy and/or shorten treatment durations even further. Thus, the combination of sofosbuvir and the 3D or 2D regimen is currently being evaluated in HCV GT1-, GT2-, and GT3-infected patients in clinical studies. The safety and pharmacokinetics of these drugs in combination were assessed in healthy volunteers. This evaluation was warranted to guide future dosing and support clinical trials of these combinations in HCV-infected subjects.

The likelihood of a clinically meaningful drug interaction between these regimens was considered low. Cytochrome P450 (CYP450) 3A4 isoenzyme is primarily responsible for the metabolism of paritaprevir, ritonavir, and to a lesser extent dasabuvir, which is primarily metabolized by CYP2C8 (10, 11). Ombitasvir is metabolized by amide hydrolysis. Ritonavir is a potent CYP450 3A4 inhibitor. Neither sofosbuvir nor its metabolites are substrates or inhibitors of CYP450 enzymes. However, sofosbuvir and GS-331007 are substrates for P-gp and BCRP transporters, which are inhibited by paritaprevir, ritonavir, and dasabuvir.

Changes in ombitasvir, paritaprevir, ritonavir, or dasabuvir pharmacokinetic exposures were ≤20% when the 3D or 2D regimen was administered with sofosbuvir. Although paritaprevir exposures decreased 15 to 19% and ritonavir exposures decreased 11 to 14%, the variability in paritaprevir exposures was high (approximately 60 to 125%). The mechanism for this decrease is not clear, and this decrease is not considered clinically relevant.

Coadministration of multiple doses of sofosbuvir with the 3D or 2D regimen resulted in a 61% to 64% increase in sofosbuvir C_max and 93% to 112% increase in AUC compared to sofosbuvir alone. GS-331007 C_max was similar with and without the DAA regimen, but the AUC was 27% to 32% higher and the C_trough was 71% to 77% higher. Sofosbuvir is a prodrug for the intracellular active moiety sofosbuvir triphosphate, which is ultimately dephosphorylated in the hepatocyte to GS-331007 before exiting the hepatocyte into the plasma. Sofosbuvir that is not taken up by hepatocytes can also be converted in the plasma to GS-331007, the predominating metabolite circulating in the plasma. Since plasma GS-331007 is formed via two mechanisms, a 2-fold increase in sofosbuvir C_max and AUC would not necessarily double the exposures of GS-331007. The increase in sofosbuvir concentrations may increase the sofosbuvir uptake by hepatocytes, but the drug may stay in mono-, di-, or triphosphate form and not be broken down to GS-331007. Intracellular hepatocyte concentrations of sofosbuvir mono-, di-, and triphosphates, which are challenging to collect and measure in a clinical setting, would be required to understand this mechanism.

Sofosbuvir is a substrate of P-gp and BCRP, whereas GS-331007, the major circulating plasma metabolite, is not a substrate of transporters. Increases in sofosbuvir C_max and AUC are likely a result of BCRP and/or P-gp transporter inhibition by paritaprevir, dasabuvir, and ritonavir. Though paritaprevir, dasabuvir, and ritonavir are all in vitro inhibitors of P-gp and BCRP, the comparable magnitude of interaction between the 2D and 3D regimen suggests that the increase in sofosbuvir is probably mediated by paritaprevir and ritonavir and not dasabuvir. In the presence of cyclosporine, sofosbuvir C_max and AUC increased 154% and 353%, respectively; however, no dose adjustment of sofosbuvir is required (8). Changes in sofosbuvir exposures during coadministration with the 3D or 2D regimens are smaller than changes observed during its coadministration with cyclosporine. The GS-331007 AUC increased 24% in the presence of 800/100 mg darunavir-ritonavir QD, and no dose adjustment of sofosbuvir is required. Changes in GS-331007 exposures during coadministration with the 2D or 3D regimen were comparable to the changes observed during its coadministration with ritonavir-boosted darunavir (8). Therefore, the increase in sofosbuvir or GS-331007 exposures in the presence of 3D or 2D does not warrant a dose adjustment of sofosbuvir.

Coadministration of the 3D or 2D regimen with sofosbuvir for 7 to 14 days was generally well tolerated by 28 healthy subjects. No new or unexpected safety findings were observed. AEs were predominantly mild, and no pattern was noted in the adverse events reported. No clinically significant hematology, serum chemistry, and urine analysis values were observed.

In summary, the lack of pharmacokinetic interaction and the favorable short-term safety profile of the 3D or 2D regimen with sofosbuvir in healthy volunteers support coadministration in HCV-infected patients enrolled in larger clinical trials. No dose adjustment is recommended for 3D, 2D, or sofosbuvir during coadministration.