PREZISTA (Page 6 of 12)

8.5 Geriatric Use

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

8.6 Hepatic Impairment

No dosage adjustment of PREZISTA/ritonavir is necessary for patients with either mild or moderate hepatic impairment. No pharmacokinetic or safety data are available regarding the use of PREZISTA/ritonavir in subjects with severe hepatic impairment. Therefore, PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30–60 mL/min, n=20). No pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end stage renal disease; however, because the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Human experience of acute overdose with PREZISTA/ritonavir is limited. No specific antidote is available for overdose with PREZISTA. Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since PREZISTA is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

11 DESCRIPTION

PREZISTA (darunavir) is an inhibitor of the human immunodeficiency virus (HIV-1) protease.

PREZISTA tablets and oral suspension contain the active ingredient darunavir, (present as darunavir ethanolate) which has the following chemical name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate. Its molecular formula is C27 H37 N3 O7 S ∙ C2 H5 OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:

Chemical Structure
(click image for full-size original)

Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.15 mg per mL in water at 20°C.

PREZISTA® 100 mg per mL oral suspension is available as a white to off-white opaque suspension for oral administration.

Each mL of the oral suspension contains darunavir 100 mg (present as darunavir ethanolate). In addition, each mL contains the inactive ingredients citric acid monohydrate, hydrochloric acid (for pH adjustment), hydroxypropyl cellulose, masking flavor, methylparaben sodium, microcrystalline cellulose, purified water, sodium carboxymethylcellulose, strawberry cream flavor and sucralose.

PREZISTA® 75 mg tablets are available as white, caplet-shaped, film-coated tablets for oral administration. Each 75 mg tablet contains darunavir 75 mg (present as darunavir ethanolate).

PREZISTA® 150 mg tablets are available as white, oval-shaped, film-coated tablets for oral administration. Each 150 mg tablet contains darunavir 150 mg (present as darunavir ethanolate).

PREZISTA® 600 mg tablets are available as orange, oval-shaped, film-coated tablets for oral administration. Each 600 mg tablet contains darunavir 600 mg (present as darunavir ethanolate).

PREZISTA® 800 mg tablets are available as dark red, oval-shaped, film-coated tablets for oral administration. Each 800 mg tablet contains darunavir 800 mg (present as darunavir ethanolate).

During storage, partial conversion from ethanolate to hydrate may occur; however, this does not affect product quality or performance. Each tablet also contains the inactive ingredients colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The 800 mg tablet also contains hypromellose. The 75 and 150 mg tablet film coating, OPADRY® White, contains polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide. The 600 mg tablet film coating, OPADRY® Orange, contains FD&C Yellow No. 6, polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide. The 800 mg tablet film coating, OPADRY® Dark Red, contains iron oxide red, polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.

All strengths for PREZISTA are expressed in terms of the free form of darunavir.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Darunavir is an HIV-1 antiviral drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT/QTc study in 40 healthy subjects, PREZISTA/ritonavir doses of 1.33 times the maximum recommended dose did not affect the QT/QTc interval.

12.3 Pharmacokinetics

Pharmacokinetics in Adults

General

Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of PREZISTA 600 mg was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir. Therefore, PREZISTA should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.

The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), has been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 11 displays the population pharmacokinetic estimates of darunavir after oral administration of PREZISTA/ritonavir 600/100 mg twice daily (based on sparse sampling in 285 patients in trial TMC114-C214, 278 patients in trial TMC114-C229 and 119 patients [integrated data] from trials TMC114-C202 and TMC114-C213) and PREZISTA/ritonavir 800/100 mg once daily (based on sparse sampling in 335 patients in trial TMC114-C211 and 280 patients in trial TMC114-C229) to HIV-1-infected patients.

Table 11: Population Pharmacokinetic Estimates of Darunavir at PREZISTA/ritonavir 800/100 mg Once Daily (Trial TMC114-C211, 48-Week Analysis and Trial TMC114-C229, 48-Week Analysis) and PREZISTA/ritonavir 600/100 mg Twice Daily (Trial TMC114-C214, 48-Week Analysis, Trial TMC114-C229, 48-Week Analysis and Integrated Data from Trials TMC114-C213 and TMC114-C202, Primary 24-Week Analysis)
PREZISTA/ritonavir800/100 mg once daily PREZISTA/ritonavir600/100 mg twice daily
Parameter TMC114-C211 N=335 TMC114-C229 N=280 TMC114-C214 N=285 TMC114-C229 N=278 TMC114-C213 + TMC114-C202 (integrated data)N=119
N=number of subjects with data
*
AUC24h is calculated as AUC12h *2.
AUC24h (ng.h/mL)*
Mean ± Standard Deviation 93026 ± 27050 93334 ± 28626 116796 ± 33594 114302 ± 32681 124698 ± 32286
Median (Range) 87854 (45000–219240) 87788 (45456–236920) 111632 (64874–355360) 109401 (48934–323820) 123336 (67714–212980)
C0h (ng/mL)
Mean ± Standard Deviation 2282 ± 1168 2160 ± 1201 3490 ± 1401 3386 ± 1372 3578 ± 1151
Median (Range) 2041 (368–7242) 1896 (184–7881) 3307 (1517–13198) 3197 (250–11865) 3539 (1255–7368)

Absorption and Bioavailability

Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a Tmax of approximately 2.5–4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data suggest that PREZISTA/ritonavir is an inhibitor of the P-glycoprotein (P-gp) transporters.

Effects of Food on Oral Absorption

When PREZISTA tablets were administered with food, the Cmax and AUC of darunavir, co-administered with ritonavir, is approximately 40% higher relative to the fasting state. Within the range of meals studied, darunavir exposure is similar. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).

Distribution

Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

Metabolism

In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after a single dose administration of 400 mg 14 C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV-1.

Elimination

A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14 C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14 C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.

Special Populations

Hepatic Impairment

Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of PREZISTA/ritonavir 600/100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].

Hepatitis B or Hepatitis C Virus Co-infection

The 48-week analysis of the data from Studies TMC114-C211 and TMC114-C214 in HIV-1-infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.

Renal Impairment

Results from a mass balance study with 14 C-PREZISTA/ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1-infected subjects with moderate renal impairment (CrCL between 30–60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1-infected patients with severe renal impairment or end stage renal disease [see Use in Specific Populations (8.7)].

Gender

Population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1-infected females compared to males. This difference is not clinically relevant.

Race

Population pharmacokinetic analysis of darunavir in HIV-1-infected subjects indicated that race had no apparent effect on the exposure to darunavir.

Geriatric Patients

Population pharmacokinetic analysis in HIV-1-infected subjects showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-1-infected subjects (n=12, age greater than or equal to 65) [see Use in Specific Populations (8.5)].

Pediatric Patients

PREZISTA/ritonavir administered twice daily

The pharmacokinetics of darunavir in combination with ritonavir in 93 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg showed that the administered weight-based dosages resulted in similar darunavir exposure when compared to the darunavir exposure achieved in treatment-experienced adults receiving PREZISTA/ritonavir 600/100 mg twice daily [see Dosage and Administration (2.5)].

PREZISTA/ritonavir administered once daily

The pharmacokinetics of darunavir in combination with ritonavir in 12 antiretroviral treatment-naïve HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 40 kg receiving PREZISTA/ritonavir 800/100 mg once daily resulted in similar darunavir exposures when compared to the darunavir exposure achieved in treatment-naïve adults receiving PREZISTA/ritonavir 800/100 mg once daily [see Dosage and Administration (2.5)].

Based on population pharmacokinetic modeling and simulation, the proposed PREZISTA/ritonavir once daily dosing regimens for pediatric patients 3 to less than 12 years of age is predicted to result in similar darunavir exposures when compared to the darunavir exposures achieved in treatment-naïve adults receiving PREZISTA/ritonavir 800/100 mg once daily [see Dosage and Administration (2.5)].

The population pharmacokinetic parameters in pediatric subjects with PREZISTA/ritonavir administered once or twice daily are summarized in the table below:

Table 12: Population Pharmacokinetic Estimates of Darunavir Exposure (Trials TMC114-C230, TMC114-C212 and TMC114-C228) Following Administration of Doses in Tables 2 and 3
PREZISTA/ritonavironce daily PREZISTA/ritonavirtwice daily
TMC114-C228*
Parameter TMC114-C230N=12 TMC114-C212N=74
10 to less than 15 kg N=10 15 to less than 20 kg §N=13
N=number of subjects with data.
*
Subjects may have contributed pharmacokinetic data to both the 10 kg to less than 15 kg weight group and the 15 kg to less than 20 kg weight group.
Summary statistics for population pharmacokinetic parameter estimates for DRV after administration of DRV/rtv at 800/100 mg once daily in treatment-naïve HIV-1 infected subjects from 12 to <18 years of age – Week-48 Analyses.
Calculated from individual pharmacokinetic parameters estimated for Week 2 and Week 4, based on the Week 48 analysis that evaluated a darunavir dose of 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily.
§
The 15 kg to less than 20 kg weight group received 380 mg (3.8 mL) PREZISTA oral suspension twice daily with 48 mg (0.6 mL) ritonavir oral solution twice daily in TMC114-C228. Calculated from individual pharmacokinetic parameters estimated for Week 2 post-dose adjustment visit; Week 24 and Week 48 based on the – Week 48 analysis that evaluated a darunavir dose of 380 mg twice daily.
AUC24h is calculated as AUC12h *2.
AUC24h (ng∙h/mL)
Mean ± Standard Deviation 84390 ± 23587 126377 ± 34356 137896 ± 51420 157760 ± 54080
Median (Range) 86741 (35527–123325) 127340 (67054–230720) 124044 (89688–261090) 132698 (112310–294840)
C0h (ng/mL)
Mean ± Standard Deviation 2141 ± 865 3948 ± 1363 4510 ± 2031 4848 ± 2143
Median (Range) 2234 (542–3776) 3888 (1836–7821) 4126 (2456–9361) 3927 (3046–10292)

Pregnancy and Postpartum

The exposure to total darunavir and ritonavir after intake of PREZISTA/ritonavir 600/100 mg twice daily and PREZISTA/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum (see Table 13, Table 14 and Figure 1).

Table 13: Pharmacokinetic Results of Total Darunavir After Administration of PREZISTA/ritonavir at 600/100 mg Twice Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum
Pharmacokinetics of total darunavir(mean ± standard deviation)2nd Trimester of pregnancy(n=12)*3rd Trimester of pregnancy(n=12)Postpartum (6–12 Weeks)(n=12)
*
n=11 for AUC24h
AUC24h is calculated as AUC12h *2.
Cmax , ng/mL4668 ± 10975328 ± 16316659 ± 2364
AUC24h , ng.h/mL 78740 ± 1919491760 ± 34720113780 ± 52680
Cmin , ng/mL 1922 ± 8252661 ± 12692851 ± 2216
Table 14: Pharmacokinetic Results of Total Darunavir After Administration of PREZISTA/ritonavir at 800/100 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum
Pharmacokinetics of total darunavir(mean ± standard deviation)2nd Trimester of pregnancy(n=17)3rd Trimester of pregnancy(n=15)Postpartum (6–12 Weeks)(n=16)
Cmax , ng/mL4964 ± 15055132 ± 11987310 ± 1704
AUC24h , ng.h/mL62289 ± 1623461112 ± 1379092116 ± 29241
Cmin , ng/mL 1248 ± 5421075 ± 5941473 ± 1141

Due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum, unbound darunavir exposures were less reduced during pregnancy as compared to postpartum. Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen (see Figure 1).

Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir After Administration of PREZISTA/ritonavir at 600/100 mg Twice Daily or 800/100 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd and 3rd Trimester of Pregnancy Compared to Postpartum

Legend: 90% CI: 90% confidence interval; GMR: geometric mean ratio. Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.
Figure 1
(click image for full-size original)

Drug Interactions

[ See also Contraindications (4), Warnings and Precautions (5.5) and Drug Interactions (7).]

Darunavir co-administered with ritonavir is an inhibitor of CYP3A, CYP2D6, and P-gp. Co-administration of darunavir and ritonavir with drugs primarily metabolized by CYP3A and CYP2D6, or are transported by P-gp, may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events.

Darunavir and ritonavir are metabolized by CYP3A. In vitro data indicate that darunavir may be a P-gp substrate. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A or P-gp may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir.

Drug interaction studies were performed with darunavir and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of darunavir on the AUC, Cmax , and Cmin values are summarized in Table 15 (effect of other drugs on darunavir) and Table 16 (effect of darunavir on other drugs). For information regarding clinical recommendations, see Drug Interactions (7).

Several interaction studies have been performed with a dose other than the recommended dose of the co-administered drug or darunavir; however, the results are applicable to the recommended dose of the co-administered drug and/or darunavir.

Table 15: Drug Interactions: Pharmacokinetic Parameters for Darunavir in the Presence of Co-Administered Drugs
Co-administered drug Dose/Schedule N PK LS Mean ratio (90% CI) of darunavirPharmacokinetic parameters with/without co-administered drugno effect =1.00
Co-administered Drug Darunavir/ritonavir Cmax AUC Cmin
N = number of subjects with data
*
q.d. = once daily
b.i.d. = twice daily
The pharmacokinetic parameters of darunavir in this study were compared with the pharmacokinetic parameters following administration of PREZISTA/ritonavir 600/100 mg twice daily.
§
Ratio based on between-study comparison.
The dose of simeprevir in this interaction study was 50 mg when co-administered in combination with PREZISTA/ritonavir compared to 150 mg once daily in the simeprevir alone treatment group.
#
Maximum number of subjects
Þ
q.o.d. = every other day
Co-administration with other HIV protease inhibitors
Atazanavir 300 mg q.d.* 400/100 mg b.i.d. 13 1.02(0.96–1.09) 1.03(0.94–1.12) 1.01(0.88–1.16)
Indinavir 800 mg b.i.d. 400/100 mg b.i.d. 9 1.11(0.98–1.26) 1.24(1.09–1.42) 1.44(1.13–1.82)
Lopinavir/ritonavir 400/100 mg b.i.d. 1200/100 mg b.i.d. 14 0.79(0.67–0.92) 0.62(0.53–0.73) 0.49(0.39–0.63)
533/133.3 mg b.i.d. 1200 mg b.i.d. 15 0.79(0.64–0.97) 0.59(0.50–0.70) 0.45(0.38–0.52)
Saquinavir hard gel capsule 1000 mg b.i.d. 400/100 mg b.i.d. 14 0.83(0.75–0.92) 0.74(0.63–0.86) 0.58(0.47–0.72)
Co-administration with other HIV antiretrovirals
Didanosine 400 mg q.d. 600/100 mg b.i.d. 17 0.93(0.86–1.00) 1.01(0.95–1.07) 1.07(0.95–1.21)
Efavirenz 600 mg q.d. 300/100 mg b.i.d. 12 0.85(0.72–1.00) 0.87(0.75–1.01) 0.69(0.54–0.87)
Etravirine 200 mg b.i.d. 600/100 mg b.i.d. 15 1.11(1.01–1.22) 1.15(1.05–1.26) 1.02(0.90–1.17)
Nevirapine 200 mg b.i.d. 400/100 mg b.i.d. 8 1.40 §(1.14–1.73) 1.24 §(0.97–1.57) 1.02 §(0.79–1.32)
Rilpivirine 150 mg q.d. 800/100 mg q.d. 15 0.90 (0.81–1.00) 0.89 (0.81–0.99) 0.89 (0.68–1.16)
Tenofovir disoproxil fumarate 300 mg q.d. 300/100 mg b.i.d. 12 1.16(0.94–1.42) 1.21(0.95–1.54) 1.24(0.90–1.69)
Co-administration with HCV NS3-4A protease inhibitors
Simeprevir 50 mg q.d. 800 mg q.d. 25# 1.04(0.99–1.10) 1.18(1.11–1.25) 1.31 (1.13–1.52)
Co-administration with other drugs
Artemether/lumefantrine 80/480 mg (6 doses at 0, 8, 24, 36, 48, and 60 hours) 600/100 mg b.i.d. 14 1.00(0.93–1.07) 0.96(0.90–1.03) 0.87(0.77–0.98)
Carbamazepine 200 mg b.i.d. 600/100 mg b.i.d. 16 1.04(0.93–1.16) 0.99(0.90–1.08) 0.85(0.73–1.00)
Clarithromycin 500 mg b.i.d. 400/100 mg b.i.d. 17 0.83(0.72–0.96) 0.87(0.75–1.01) 1.01(0.81–1.26)
Ketoconazole 200 mg b.i.d. 400/100 mg b.i.d. 14 1.21(1.04–1.40) 1.42(1.23–1.65) 1.73(1.39–2.14)
Omeprazole 20 mg q.d. 400/100 mg b.i.d. 16 1.02(0.95–1.09) 1.04(0.96–1.13) 1.08(0.93–1.25)
Paroxetine 20 mg q.d. 400/100 mg b.i.d. 16 0.97(0.92–1.02) 1.02(0.95–1.10) 1.07(0.96–1.19)
Pitavastatin 4 mg q.d. 800/100 mg q.d. 27 1.06(1.00–1.12) 1.03(0.95–1.12) NA
Ranitidine 150 mg b.i.d. 400/100 mg b.i.d. 16 0.96(0.89–1.05) 0.95(0.90–1.01) 0.94(0.90–0.99)
Rifabutin 150 mg q.o.d.Þ 600/100 mg b.i.d. 11 1.42(1.21–1.67) 1.57(1.28–1.93) 1.75(1.28–2.37)
Sertraline 50 mg q.d. 400/100 mg b.i.d. 13 1.01(0.89–1.14) 0.98(0.84–1.14) 0.94(0.76–1.16)
Table 16: Drug Interactions: Pharmacokinetic Parameters for Co-Administered Drugs in the Presence of PREZISTA/ritonavir
Co-administered drug Dose/Schedule N PK LS Mean ratio (90% CI) of co-administered drugpharmacokinetic parameters with/without darunavirno effect =1.00
Co-administered drug Darunavir/ritonavir Cmax AUC Cmin
N = number of subjects with data;- = no information availableA cocktail study was conducted in 12 healthy volunteers to evaluate the effect of steady state pharmacokinetics of PREZISTA/ritonavir on the activity of CYP2D6 (using dextromethorphan as probe substrate), CYP2C9 (using warfarin as probe substrate), and CYP2C19 (using omeprazole as probe substrate). The pharmacokinetic results are shown in Table 16.
*
q.d. = once daily
b.i.d. = twice daily
The pharmacokinetic parameters of lopinavir in this study were compared with the pharmacokinetic parameters following administration of lopinavir/ritonavir 400/100 mg twice daily.
§
Noted as Cτ or C24 in the dolutegravir U.S. prescribing information
The dose of simeprevir in this interaction study was 50 mg when co-administered in combination with PREZISTA/ritonavir compared to 150 mg once daily in the simeprevir alone treatment group.
#
Maximum number of subjects
Þ
ratio is for buprenorphine; mean Cmax and AUC24 for naloxone were comparable when buprenorphine/naloxone was administered with or without PREZISTA/ritonavir
ß
q.o.d. = every other day
à
In comparison to rifabutin 300 mg once daily.
Co-administration with other HIV protease inhibitors
Atazanavir 300 mg q.d.* /100 mg ritonavir q.d. when administered alone 400/100 mg b.i.d. 13 0.89(0.78–1.01) 1.08(0.94–1.24) 1.52(0.99–2.34)
300 mg q.d. when administered with darunavir/ritonavir
Indinavir 800 mg b.i.d. /100 mg ritonavir b.i.d. when administered alone 400/100 mg b.i.d. 9 1.08(0.95–1.22) 1.23(1.06–1.42) 2.25(1.63–3.10)
800 mg b.i.d. when administered with darunavir/ ritonavir
Lopinavir/ritonavir 400/100 mg b.i.d. 1200/100 mg b.i.d. 14 0.98(0.78–1.22) 1.09(0.86–1.37) 1.23(0.90–1.69)
533/133.3 mg b.i.d. 1200 mg b.i.d. 15 1.11(0.96–1.30) 1.09(0.96–1.24) 1.13(0.90–1.42)
Saquinavir hard gel capsule 1000 mg b.i.d. /100 mg ritonavir b.i.d. when administered alone 400/100 mg b.i.d. 12 0.94(0.78–1.13) 0.94(0.76–1.17) 0.82(0.52–1.30)
1000 mg b.i.d. when administered with darunavir/ritonavir
Co-administration with other HIV antiretrovirals
Didanosine 400 mg q.d. 600/100 mg b.i.d. 17 0.84(0.59–1.20) 0.91(0.75–1.10)
Dolutegravir 30 mg q.d 600/100 mg b.i.d. 15 0.89(0.83–0.97) 0.78(0.72–0.85) 0.62§(0.56–0.69)
Dolutegravir 50 mg q.d. 600/100 mg b.i.d. with 200 mg b.i.d. etravirine 9 0.88(0.78–1.00) 0.75(0.69–0.81) 0.63 §(0.52–0.76)
Efavirenz 600 mg q.d. 300/100 mg b.i.d. 12 1.15(0.97–1.35) 1.21(1.08–1.36) 1.17(1.01–1.36)
Etravirine 100 mg b.i.d. 600/100 mg b.i.d. 14 0.68(0.57–0.82) 0.63(0.54–0.73) 0.51(0.44–0.61)
Nevirapine 200 mg b.i.d. 400/100 mg b.i.d. 8 1.18(1.02–1.37) 1.27(1.12–1.44) 1.47(1.20–1.82)
Rilpivirine 150 mg q.d. 800/100 mg q.d. 14 1.79 (1.56–2.06) 2.30 (1.98–2.67) 2.78 (2.39–3.24)
Tenofovir disoproxil fumarate 300 mg q.d. 300/100 mg b.i.d. 12 1.24(1.08–1.42) 1.22(1.10–1.35) 1.37(1.19–1.57)
Maraviroc 150 mg b.i.d. 600/100 mg b.i.d. 12 2.29(1.46–3.59) 4.05(2.94–5.59) 8.00(6.35–10.1)
600/100 mg b.i.d. with 200 mg b.i.d. etravirine 10 1.77(1.20–2.60) 3.10(2.57–3.74) 5.27(4.51–6.15)
Co-administration with HCV NS3-4A protease inhibitors
Simeprevir 50 mg q.d. 800/100 mg q.d. 25# 1.79 (1.55–2.06) 2.59 (2.15–3.11) 4.58 (3.54–5.92)
Co-administration with other drugs
Atorvastatin 40 mg q.d. when administered alone 300/100 mg b.i.d. 15 0.56(0.48–0.67) 0.85(0.76–0.97) 1.81(1.37–2.40)
10 mg q.d. when administered with darunavir/ritonavir
Artemether 80 mg single dose 600/100 mg b.i.d. 15 0.85(0.68–1.05) 0.91(0.78–1.06)
Dihydroartemisinin 15 1.06(0.82–1.39) 1.12(0.96–1.30)
Artemether artemether/lumefantrine 80/480 mg (6 doses at 0, 8, 24, 36, 48, and 60 hours) 600/100 mg b.i.d. 15 0.82(0.61–1.11) 0.84(0.69–1.02) 0.97(0.90–1.05)
Dihydroartemisinin 15 0.82(0.66–1.01) 0.82(0.74–0.91) 1.00(0.82–1.22)
Lumefantrine 15 1.65(1.49–1.83) 2.75(2.46–3.08) 2.26(1.92–2.67)
Buprenorphine/Naloxone 8/2 mg to 16/4 mg q.d. 600/100 mg b.i.d. 17 0.92 Þ(0.79–1.08) 0.89 Þ(0.78–1.02) 0.98 Þ(0.82–1.16)
Norbuprenorphine 17 1.36(1.06–1.74) 1.46(1.15–1.85) 1.71(1.29–2.27)
Carbamazepine 200 mg b.i.d. 600/100 mg b.i.d. 16 1.43(1.34–1.53) 1.45(1.35–1.57) 1.54(1.41–1.68)
Carbamazepine epoxide 16 0.46(0.43–0.49) 0.46(0.44–0.49) 0.48(0.45–0.51)
Clarithromycin 500 mg b.i.d. 400/100 mg b.i.d. 17 1.26(1.03–1.54) 1.57(1.35–1.84) 2.74(2.30–3.26)
Dextromethorphan 30 mg 600/100 mg b.i.d. 12 2.27(1.59–3.26) 2.70(1.80–4.05)
Dextrorphan 0.87(0.77–0.98) 0.96(0.90–1.03)
Digoxin 0.4 mg 600/100 mg b.i.d. 8 1.15 (0.89–1.48) 1.36 (0.81–2.27)
Ethinyl estradiol (EE) Ortho-Novum 1/35(35 µg EE /1 mg NE) 600/100 mg b.i.d. 11 0.68(0.61–0.74) 0.56(0.50–0.63) 0.38(0.27–0.54)
Norethindrone (NE) 11 0.90(0.83–0.97) 0.86(0.75–0.98) 0.70(0.51–0.97)
Ketoconazole 200 mg b.i.d. 400/100 mg b.i.d. 15 2.11(1.81–2.44) 3.12(2.65–3.68) 9.68(6.44–14.55)
R-Methadone 55–150 mg q.d. 600/100 mg b.i.d. 16 0.76(0.71–0.81) 0.84(0.78–0.91) 0.85(0.77–0.94)
Omeprazole 40 mg single dose 600/100 mg b.i.d. 12 0.66(0.48–0.90) 0.58(0.50–0.66)
5-hydroxy omeprazole 0.93(0.71–1.21) 0.84(0.77–0.92)
Paroxetine 20 mg q.d. 400/100 mg b.i.d. 16 0.64(0.59–0.71) 0.61(0.56–0.66) 0.63(0.55–0.73)
Pitavastatin 4 mg q.d. 800/100 mg q.d. 27 0.96(0.84–1.09) 0.74(0.69–0.80) NA
Pravastatin 40 mg single dose 600/100 mg b.i.d. 14 1.63(0.95–2.82) 1.81(1.23–2.66)
Rifabutin 150 mg q.o.d. ß when administered with PREZISTA/ritonavir 600/100 mg b.i.d. à 11 0.72(0.55–0.93) 0.93(0.80–1.09) 1.64(1.48–1.81)
25-O -desacetyl-rifabutin 300 mg q.d. when administered alone 11 4.77(4.04–5.63) 9.81(8.09–11.9) 27.1(22.2–33.2)
Sertraline 50 mg q.d. 400/100 mg b.i.d. 13 0.56 (0.49–0.63) 0.51 (0.46–0.58) 0.51 (0.45–0.57)
Sildenafil 100 mg (single dose) administered alone 400/100 mg b.i.d. 16 0.62(0.55–0.70) 0.97(0.86–1.09)
25 mg (single dose)when administered with darunavir/ritonavir
S-warfarin 10 mg single dose 600/100 mg b.i.d. 12 0.92(0.86–0.97) 0.79(0.73–0.85)
7-OH-S-warfarin 12 1.42(1.24–1.63) 1.23(0.97–1.57)

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