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2014年9月24日,FDA批准吉利德公司的Tybost(cobicistat)150毫克片剂，一种CYP3A抑制剂，通过与阿扎那韦或达芦那韦联合用药治疗1型人类免疫缺陷病毒(HIV-1)感染。
Coadministration with tenofovir DF: assess estimated creatinine clearance, urine glucose, and urine protein at baseline. (2.2) TYBOST coadministered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST. (2.3) DOSAGE FORMS AND STRENGTHS Tablets: 150 mg. (3) CONTRAINDICATIONS Coadministration with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect. (4) WARNINGS AND PRECAUTIONS Assess creatinine clearance (CLcr) before initiating treatment. (5.1) When TYBOST is used in combination with a tenofovir disoproxil fumarate (tenofovir DF) containing regimen, cases of acute renal failure and Fanconi syndrome have been reported. (5.2) Use with tenofovir DF: Assess urine glucose and urine protein at baseline and monitor CLcr, urine glucose, and urine protein. Monitor serum phosphorus in patients with or at risk for renal impairment. (5.2) TYBOST in combination with more than one antiretroviral that requires pharmacokinetic enhancement (i.e., two protease inhibitors or elvitegravir in combination with a protease inhibitor) is not recommended. (5.4) Use with HIV-1 protease inhibitors other than atazanavir or darunavir administered once daily are not recommended. (5.4) Coadministration with cobicistat-containing drugs, including STRIBILD®, is not recommended. (5.4) Coadministration with drugs or regimens containing ritonavir is not recommended. (5.4) ADVERSE REACTIONS The most common adverse drug reactions observed with TYBOST in combination with atazanavir (incidence greater than 5%, Grades 2–4) are jaundice and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS TYBOST, in combination with atazanavir or darunavir, can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of TYBOST, atazanavir and darunavir. Consult the full prescribing information prior to and during treatment for potential drug interactions. (4, 5.3, 7, 12.3) USE IN SPECIFIC POPULATIONS Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk. (8.1) Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 12/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection [see Dosage and Administration (2.1)]. Limitations of Use: TYBOST is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data. The use of TYBOST is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir [see Warnings and Precautions (5.4)]. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions. TYBOST and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications [see Warnings and Precautions (5.3), Drug Interactions (7), and Clinical Pharmacology (12.3)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of adults with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are presented in Table 1. TYBOST must be coadministered at the same time as atazanavir or darunavir [see Drug Interactions (7)]. Consult the prescribing information for atazanavir or darunavir. Table 1 Recommended Dosing Regimens
Prior to starting TYBOST, assess estimated creatinine clearance because TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1)]. When coadministering TYBOST with tenofovir disoproxil fumarate (tenofovir DF), assess estimated creatinine clearance, urine glucose, and urine protein at baseline [see Warnings and Precautions 5.2]. 2.3 Renal Impairment TYBOST coadministered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. 3 DOSAGE FORMS AND STRENGTHS Orange, round, biconvex, film-coated tablets debossed with "GSI" on one side and plain faced on the other side providing 150 mg of cobicistat. 4 CONTRAINDICATIONS The concomitant use of TYBOST with atazanavir or darunavir and the following drugs (see Table 2) is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions (7.1, 7.2)]. Table 2 Drugs that are Contraindicated with Concomitant use with TYBOST and Atazanavir or Darunavir
See Drug Interactions (7), Table 6 for parenterally administered midazolam. 5 WARNINGS AND PRECAUTIONS 5.1 Effects on Serum Creatinine TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating TYBOST, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. Prior to initiating therapy with TYBOST, assess estimated creatinine clearance [see Dosage and Administration (2.2)]. Dosage recommendations are not available for drugs that require dosage adjustments in TYBOST-treated patients with renal impairment [see Adverse Reactions (6.1), Drug Interactions (7.3), and Clinical Pharmacology (12.2)]. Consider alternative medications that do not require dosage adjustments in patients with renal impairment. Although TYBOST may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. 5.2 New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when TYBOST was used in an antiretroviral regimen that contained tenofovir DF. Coadministration of TYBOST and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST [see Dosage and Administration (2.2, 2.3)]. Document urine glucose and urine protein at baseline [see Dosage and Administration (2.2)] and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when TYBOST is used with tenofovir DF. Measure serum phosphorus in patients with or at risk for renal impairment when used with tenofovir DF. Coadministration of TYBOST and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended. In a clinical trial of TYBOST over 144 weeks (N=692), 10 (2.9%) subjects treated with TYBOST coadministered with atazanavir and TRUVADA® and 11 (3.2%) subjects treated with ritonavir coadministered with atazanavir and TRUVADA discontinued study drug due to a renal adverse event. Seven of the 10 subjects (2.0% overall) in the TYBOST group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation compared to 7 of 11 subjects (2.0% overall) in the ritonavir group. One subject in the TYBOST group had renal impairment at baseline (i.e., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of TYBOST coadministered with atazanavir and TRUVADA. Renal replacement therapy was not required in any subject. 5.3 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions Initiation of TYBOST, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving TYBOST may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of TYBOST with atazanavir or darunavir. Increased concentrations may lead to: clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from higher exposures of concomitant medications. clinically significant adverse reactions from higher exposures of TYBOST and atazanavir or darunavir. Decreased antiretroviral concentrations may lead to: loss of therapeutic effect of TYBOST with atazanavir or darunavir and possible development of resistance. See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during TYBOST with atazanavir or darunavir therapy; review concomitant medications during TYBOST with atazanavir or darunavir therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)]. TYBOST or ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions [see Drug Interactions (7), and Clinical Pharmacology (12.3)]. 5.4 Antiretrovirals that are Not Recommended The following antiretrovirals are not recommended in combination with TYBOST because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance: More than one antiretroviral that requires pharmacokinetic enhancement (i.e., two protease inhibitors or a protease inhibitor in combination with elvitegravir) Darunavir in combination with efavirenz, nevirapine, or etravirine Atazanavir in combination with etravirine Atazanavir in combination with efavirenz in treatment-experienced patients Darunavir 600 mg twice daily Other HIV-1 protease inhibitors including fosamprenavir, saquinavir, or tipranavir TYBOST in combination with STRIBILD® fixed-dose combination tablets (elvitegravir, cobicistat, emtricitabine, tenofovir DF) is not recommended because cobicistat is a component of STRIBILD. TYBOST in combination with lopinavir/ritonavir or regimens containing ritonavir is not recommended due to similar effects of TYBOST and ritonavir on CYP3A. 6 ADVERSE REACTIONS The following adverse reaction is described in greater detail in another section of the labeling: New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate [see Warnings and Precautions (5.2)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of TYBOST is based on Week 144 data from a Phase 3 trial, Study 114, in which 692 HIV-1 infected, antiretroviral treatment-naïve subjects received: TYBOST coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA) (N=344) or; ritonavir coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA) (N=348). The most common adverse reactions (Grades 2–4) and reported in >5% of subjects in the TYBOST group were jaundice (6%), and rash (5%). The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 11% in both the TYBOST and ritonavir groups. Table 3 displays the frequency of adverse reactions (Grades 2–4) occurring in at least 2% of subjects in the TYBOST group in Study 114. Table 3 Selected Adverse Reactions* (Grades 2–4) Reported in ≥2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Study 114 (Week 144 Analysis)
Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, and urticaria. Less Common Adverse Reactions Selected adverse reactions of at least moderate severity (≥ Grade 2) occurring in less than 2% of subjects receiving TYBOST coadministered with atazanavir and TRUVADA are listed below. These events have been included because of the investigator's assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with TYBOST and with greater frequency compared with ritonavir. Gastrointestinal Disorders: vomiting, upper abdominal pain General Disorders and Administration Site Conditions: fatigue Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis Psychiatric Disorders: depression, abnormal dreams, insomnia Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs. Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects in the TYBOST group in Study 114 is presented in Table 4. Table 4 Laboratory Abnormalities (Grades 3–4) in ≥2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Study 114 (Week 144 Analysis)
Increase in Serum Creatinine: TYBOST causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)]. In Study 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with TYBOST, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was –15.1 ± 16.5 mL/min in the TYBOST group and –8.0 ± 16.8 mL/min in the ritonavir group. Serum Lipids: Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5. In both groups, mean values for serum lipids remained within the study reference range for each laboratory test. The clinical significance of these changes is unknown. Table 5 Lipid Values, Mean Change from Baseline, Reported in HIV-1 Infected Treatment-Naïve Adults Receiving TYBOST Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir + TRUVADA in Study 114 (Week 144 Analysis)
7 DRUG INTERACTIONS See also Dosage and Administration (2), Contraindications (4), Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (12.3). 7.1 Potential Effect of Cobicistat (Coadministered with Atazanavir or Darunavir) on the Pharmacokinetics of Concomitant Drugs Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. The plasma concentration of drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may be increased if those drugs are coadministered with TYBOST. Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data. Coadministration of TYBOST with atazanavir or darunavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 6. 7.2 Potential Effect of Concomitant Drugs on the Pharmacokinetics of Cobicistat (Coadministered with Atazanavir or Darunavir) Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Atazanavir and darunavir are also metabolized by CYP3A. Coadministration of TYBOST with atazanavir or darunavir in combination with drugs that induce CYP3A activity have the potential to decrease plasma concentrations of cobicistat, atazanavir and darunavir, which may lead to loss of therapeutic effect and development of resistance (see Table 6). Coadministration of TYBOST with atazanavir or darunavir in combination with other drugs that inhibit CYP3A may further increase the plasma concentrations of cobicistat, atazanavir and darunavir (see Table 6). 7.3 Established and Other Potentially Significant Interactions Coadministration of TYBOST with fosamprenavir, saquinavir, or tipranavir is not recommended because pharmacokinetic data are not available to provide appropriate dosing recommendations. Use of TYBOST with lopinavir is not recommended because lopinavir is co-formulated with ritonavir. Drug interaction trials were not conducted for TYBOST in combination with atazanavir or darunavir. As a single entity, drug interaction trials were conducted with TYBOST and desipramine, digoxin, and efavirenz. Table 6 provides dosing recommendations as a result of drug interactions with TYBOST. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse events or loss of therapeutic effect. In Table 6, if not specifically stated, the drug interaction information applies to both coadministered agents: TYBOST coadministered with atazanavir or darunavir [see Clinical Pharmacology (12.3)]. In addition to the drug interactions noted in Table 6, TYBOST is not recommended for use in combination with STRIBILD tablets, lopinavir/ritonavir or regimens containing ritonavir, or in combination with more than one antiretroviral agent that requires pharmacokinetic enhancement [see Warnings and Precautions (5.4)]. Evaluate whether dosing adjustments of concomitant medications or coadministered antiretroviral drugs are necessary in: Patients on a stable concomitant medication who initiate or switch to a TYBOST-containing regimen Patients on a TYBOST-containing regimen who initiate a new concomitant medication Patients initiating a TYBOST-containing regimen and a new concomitant medication simultaneously Under these circumstances, also monitor for adverse events and/or monitor concentrations of concomitant medications if appropriate. No dose adjustment is required when tenofovir DF or rilpivirine are coadministered with TYBOST and atazanavir or darunavir. Table 6 Established and Other Potentially Significant* Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
↑ = Increase, ↓ = Decrease, ↔ = No change 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TYBOST during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry 1-800-258-4263. Risk Summary There are no data with TYBOST in pregnant women to inform a drug-associated risk. In animal reproduction studies in rats and rabbits, no evidence of fetal harm was observed with oral administration of cobicistat during organogenesis at doses that produced exposures up to 1.4 and 3.3-times, respectively, the maximal recommended human dose (MRHD) of 150 mg [see Data]. Consider the benefits and risks of TYBOST when prescribing TYBOST to a pregnant woman. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Because TYBOST is coadministered with atazanavir or darunavir and other antiretroviral drugs, also refer to the prescribing information of each drug for information about pregnancy. Data Animal Data Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation day 6 to 17. Maternal toxicity (adverse clinical signs, decreased body weight and food consumption) was noted at 125 mg/kg/day and was associated with increases in postimplantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females was 1.4-fold higher than the exposures at the MRHD. In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3-fold higher than exposures at the MRHD. In a pre- and postnatal developmental study, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation day 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were slightly lower than (0.9-fold) the MRHD. 8.2 Lactation Risk Summary There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant or the effects on milk production. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. 8.4 Pediatric Use Safety and effectiveness of TYBOST in pediatric patients younger than 18 years of age have not been established. 8.5 Geriatric Use Clinical trials of TYBOST did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. 8.6 Renal Impairment No dosage adjustment of TYBOST is required in patients with renal impairment, including those with severe renal impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. TYBOST is coadministered with atazanavir or darunavir; therefore, refer to the prescribing information for atazanavir or darunavir for information regarding dosing recommendations of these drugs in patients with renal impairment [see Clinical Pharmacology (12.3)]. TYBOST has been shown to decrease estimated creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosing adjustment for renal impairment when used in combination with TYBOST [see Dosage and Administration (2), Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)]. 8.7 Hepatic Impairment No dosing adjustment of TYBOST is necessary for patients with mild-to-moderate hepatic impairment. No data are available in patients with severe hepatic impairment. TYBOST is coadministered with atazanavir or darunavir and other antiretroviral drugs; therefore, refer to the prescribing information of these other drugs for information regarding dosing recommendations in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with TYBOST consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient. As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis. 11 DESCRIPTION TYBOST (cobicistat) is a mechanism-based CYP3A inhibitor. The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. It has the following structural formula:
Table 8 Pharmacokinetic Parameters (Mean ± SD) of Darunavir in Healthy Adults (Study 115)
The effect of a single dose of cobicistat 250 mg and 400 mg (approximately 1.7 and 2.7 times the recommended dose, respectively) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-period crossover thorough QT study in 48 healthy subjects. In this study, no significant QTc prolongation effect of cobicistat was detected. The dose of 400 mg TYBOST is expected to cover a high exposure clinical scenario. Prolongation of the PR interval was noted in subjects receiving TYBOST in the same study. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for 250 mg and 20.2 (22.8) msec for 400 mg of cobicistat. Effects on Serum Creatinine The effect of TYBOST on serum creatinine was investigated in a trial in subjects with normal renal function (eGFR ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50–79 mL/min, N=18). A statistically significant decrease in the estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFRCG) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (-9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (-11.9 ± 7.0 mL/min). No statistically significant changes in eGFRCG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment with TYBOST among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate [see Warnings and Precautions (5.1)]. 12.3 Pharmacokinetics Absorption In a trial where subjects were instructed to take coadministered TYBOST and darunavir with food, median cobicistat peak plasma concentrations were observed was approximately 3.5 hours post-dose. Steady-state cobicistat Cmax, AUCtau, and Ctau (mean ± SD) values were 0.99 ± 0.3 mcg/mL (n=60), 7.6 ± 3.7 mcg*hr/mL (n=59), and 0.03 ± 0.1 mcg/mL (n=59), respectively. Effect of Food on Oral Absorption A food effect trial was not conducted for TYBOST. In clinical trials, TYBOST was coadministered with other antiretroviral agents [see Clinical Studies (14)] under fed conditions, in accordance with the prescribing information for these agents. It is recommended that TYBOST coadministered with atazanavir or darunavir be administered with food [see Dosage and Administration (2.1)]. Distribution Cobicistat is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5. Metabolism Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation. Elimination The terminal plasma half-life of cobicistat following administration of TYBOST is approximately 3 to 4 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for 6 days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively. Specific Populations Patients with Hepatic Impairment Cobicistat is primarily metabolized and eliminated by the liver. A study of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied [see Use in Specific Populations (8.7)]. Patients with Renal Impairment A study of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects [see Use in Specific Populations (8.6)]. Race Population pharmacokinetic analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat. Gender No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat. Assessment of Drug Interactions Drug interaction trials were not conducted for TYBOST coadministered with atazanavir or darunavir. Drug interaction trials were conducted with TYBOST (as a single entity) and desipramine, digoxin, and efavirenz. Drug interaction trials of TYBOST coadministered with elvitegravir included rosuvastatin and rifabutin. The effects of cobicistat on the exposure of coadministered drugs are shown in Table 9. Note: The information listed below is not a comprehensive list of all the available drug interaction data for concomitant medications with cobicistat containing regimens. Please refer to the U.S. prescribing information for antiretroviral medications administered in combination with cobicistat for additional drug interaction information. Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Cobicistat*
NC = Not Calculated. 12.4 Microbiology Antiviral Activity Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat. Resistance In an analysis of treatment-failure subjects who received TYBOST coadministered with atazanavir and TRUVADA in Study 114 through Week 144, evaluable genotypic data from paired baseline and treatment-failure isolates from subjects who had HIV-1 RNA greater than or equal to 400 copies/mL were available for all 21 virologic failures in the TYBOST group [6%, 21/344]. Among the 21 subjects, 3 developed the emtricitabine-associated resistance substitution M184V. No subject developed the tenofovir-associated resistance substitution K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures [5%, 19/348]. Among the 19 patients, 1 developed the emtricitabine-associated resistance substitution M184V with no tenofovir or protease inhibitor associated resistance substitutions. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose. Mutagenesis Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma, or rat micronucleus assays. Impairment of Fertility Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose. Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose. 14 CLINICAL STUDIES The activity of TYBOST as a CYP3A inhibitor to increase the systemic exposures of atazanavir or darunavir has been demonstrated in pharmacokinetic trials. In these trials, the exposure of atazanavir or darunavir coadministered with TYBOST 150 mg was consistent with those observed with ritonavir 100 mg [see Clinical Pharmacology (12.2)]. For clinical efficacy of darunavir/ritonavir 800/100 mg once daily, refer to the prescribing information for darunavir. The safety and efficacy of TYBOST coadministered with atazanavir were evaluated in a randomized, double-blind, active-controlled trial (Study 114) in HIV-1 infected treatment-naïve subjects with baseline estimated creatinine clearance above 70 mL/min (N=692). In Study 114, subjects were randomized in a 1:1 ratio to receive either atazanavir 300 mg + TYBOST 150 mg once daily or atazanavir 300 mg + ritonavir 100 mg once daily. All subjects received concomitant treatment with 300 mg of tenofovir DF and 200 mg of emtricitabine once a day administered as single tablet TRUVADA. Randomization was stratified by screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL). The mean age of subjects was 37 years (range 19–70); 83% were male, 60% were White, 18% were Black and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range 3.2–6.4). Forty percent of patients had baseline viral loads >100,000 copies/mL. The mean baseline CD4+ cell count was 352 cells/mm3 (range 1–1455) and 17% had CD4+ cell counts ≤200 cells/mm3. Virologic outcomes in Study 114 through Week 144 are presented in Table 10. In Study 114, the mean increase from baseline in CD4+ cell count at Week 144 was 281 cells/mm3 in the TYBOST group and 297 cells/mm3 in the ritonavir group. Table 10 Virologic Outcome of Randomized Treatment of Study 114 in HIV-1 Infected Treatment Naïve Adults at Week 144*
Included subjects who had ≥50 copies/mL in the Week 144 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL. Includes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. Includes subjects who discontinued for reasons other than an AE, death, or lack or loss of efficacy; e.g., withdrew consent, lost to follow-up, etc. 16 HOW SUPPLIED/STORAGE AND HANDLING TYBOST tablets, 150 mg, are orange, round, biconvex, film-coated, and debossed with "GSI" on one side and plain faced on the other side. Each bottle contains 30 tablets (NDC 61958-1401-1) and a silica gel desiccant, with a child-resistant closure. Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature). Keep container tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.
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