ISENTRESS (Page 5 of 8)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

In a monotherapy study raltegravir (400 mg twice daily) demonstrated rapid antiviral activity with mean viral load reduction of 1.66 log 10 copies/mL by Day 10.

Cardiac Electrophysiology

At a dose 1.33 times the maximum approved recommended dose (and peak concentrations 1.25-fold higher than the maximum approved dose), raltegravir does not prolong the QT interval or PR interval to any clinically relevant extent.

12.3 Pharmacokinetics

Adults

Absorption

Raltegravir, given 400 mg twice daily, is absorbed with a T max of approximately 3 hours postdose in the fasted state in healthy subjects. Raltegravir 1200 mg once daily is rapidly absorbed with median T max of ~1.5 to 2 hours in the fasted state.

Raltegravir increases dose proportionally (AUC and C max ) or slightly less than dose proportionally (C 12hr ) over the dose range 100 mg to 1600 mg.

The absolute bioavailability of raltegravir has not been established. The chewable tablet and oral suspension have higher oral bioavailability compared to the 400 mg film-coated tablet.

Relative to the raltegravir 400 mg formulation, the raltegravir 600 mg formulation has higher relative bioavailability.

Steady-state is generally reached in 2 days, with little to no accumulation with multiple dose administration for the 400 mg twice daily and 1200 once daily formulation.

Effect of Food on Oral Absorption

The food effect of various formulations are presented in Table 12.

Table 12: Effect of Food on the Pharmacokinetics of Raltegravir Formulations
PK parameter ratio (fed/fasted)
Formulation Meal Type AUC Ratio (90% CI) C max Ratio (90% CI) C min Ratio (90% CI)
Low-fat meal: 300 Kcal, 2.5 g fat
Moderate-fat meal: 600 Kcal, 21 g fat
High-fat meal: 825 Kcal, 52 g fat
400 mg twice daily Low Fat 0.54 (0.41-0.71) 0.48 (0.35-0.67) 0.86 (0.54-1.36)
Moderate Fat 1.13 (0.85-1.49) 1.05 (0.75-1.46) 1.66 (1.04-2.64)
High Fat 2.11 (1.60-2.80) 1.96 (1.41-2.73) 4.13 (2.60-6.57)
1200 mg once daily Low Fat 0.58 (0.46-0.74) 0.48 (0.37-0.62) 0.84 (0.63-1.10)
High Fat 1.02 (0.86-1.21) 0.72 (0.58-0.90) 0.88 (0.66-1.18)
Chewable tablet High Fat 0.94 (0.78-1.14) 0.38 (0.28-0.52) 2.88 (2.21-3.75)
Oral suspension The effect of food on oral suspension was not studied.

Distribution

Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM.

In one study of HIV-1 infected subjects who received raltegravir 400 mg twice daily, raltegravir was measured in the cerebrospinal fluid. In the study (n=18), the median cerebrospinal fluid concentration was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration. This median proportion was approximately 3-fold lower than the free fraction of raltegravir in plasma. The clinical relevance of this finding is unknown.

Metabolism and Excretion

The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. The major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.

Table 13: Multiple-Dose Pharmacokinetic Parameters of Raltegravir Following the Administration of 400 mg Twice Daily and 1200 mg Once Daily in HIV-infected Subjects
Parameter 400 mg BID Geometric Mean (%CV) N=6 1200 mg QD Geometric Mean (%CV) N=524
AUC (µM∙hr) AUC 0-12 = 14.3 (88.6) AUC 0-24 = 55.3 (41.5)
C max (µM) 4.5 (128) 15.7 (45.8)
C min (nM) C 12 = 142 (63.8) C 24 = 107 (97.5)

Special Populations

Pediatric

ISENTRESS

Two pediatric formulations were evaluated in healthy adult volunteers, where the chewable tablet and oral suspension were compared to the 400 mg tablet. The chewable tablet and oral suspension demonstrated higher oral bioavailability, thus higher AUC, compared to the 400 mg tablet. In the same study, the oral suspension resulted in higher oral bioavailability compared to the chewable tablet. These observations resulted in proposed pediatric doses targeting 6 mg/kg/dose for the chewable tablets and oral suspension. As displayed in Table 13, the doses recommended for HIV-infected infants, children and adolescents 4 weeks to 18 years of age [see Dosage and Administration (2.3)] resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily.

Overall, dosing in pediatric patients achieved exposures (C trough ) above 45 nM in the majority of subjects, but some differences in exposures between formulations were observed. Pediatric patients above 25 kg administered the chewable tablets had lower trough concentrations (113 nM) compared to pediatric patients above 25 kg administered the 400 mg tablet formulation (233 nM) [see Clinical Studies (14.4)] . As a result, the 400 mg film-coated tablet is the recommended dose in patients weighing at least 25 kg; however, the chewable tablet offers an alternative regimen in patients weighing at least 25 kg who are unable to swallow the film-coated tablet [see Dosage and Administration (2.3)] . In addition, pediatric patients weighing 11 to 25 kg who were administered the chewable tablets had the lowest trough concentrations (82 nM) compared to all other pediatric subgroups.

Table 14: Raltegravir Steady State Pharmacokinetic Parameters in Pediatric Patients Following Administration of Recommended Twice-Daily Doses
Body Weight Formulation Dose N * Geometric Mean (%CV ) AUC 0-12hr (µM∙hr) Geometric Mean (%CV ) C 12hr (nM)
*
Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose.
Geometric coefficient of variation.
≥25 kg Film-coated tablet 400 mg twice daily 18 14.1 (121%) 233 (157%)
≥25 kg Chewable tablet Weight based dosing, see Table 3 9 22.1 (36%) 113 (80%)
11 to less than 25 kg Chewable tablet Weight based dosing, see Table 4 13 18.6 (68%) 82 (123%)
3 to less than 20 kg Oral suspension Weight based dosing, see Table 4 19 24.5 (43%) 113 (69%)

Elimination of raltegravir in vivo in human is primarily through the UGT1A1-mediated glucuronidation pathway. UGT1A1 catalytic activity is negligible at birth and matures after birth. The dose recommended for neonates less than 4 weeks of age takes into consideration the rapidly increasing UGT1A1 activity and drug clearance from birth to 4 weeks of age. Table 15 displays pharmacokinetic parameters for neonates receiving the granules for oral suspension at the recommended dose [see Dosage and Administration (2.3)].

Table 15: Raltegravir Pharmacokinetic Parameters from IMPAACT P1110 Following Age and Weight Based Dosing of Oral Suspension
Age (hours/days) at PK Sampling Dose (See Table 5) N * Geometric Mean (%CV ) AUC (μM∙hr ) Geometric Mean (%CV ) C trough (nM)
*
Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose.
Geometric coefficient of variation.
AUC 0-24hr (N = 24) and C 24hr
§
AUC 0-12hr and C 12hr
Birth – 48 hours 1.5 mg/kg once daily 25 85.9 (38.4%) 2132.9 (64.2%)
15 to 18 days 3.0 mg/kg twice daily 23 32.2 (43.3%) § 1255.5 (83.7%) §

ISENTRESS HD

ISENTRESS HD 1200 mg (2 × 600 mg) was not evaluated in a pediatric clinical study. Exposures for pediatric subjects weighing at least 40 kg administered ISENTRESS HD are predicted to be comparable to adult exposures observed from Phase III ONCEMRK.

Age/Race/Gender

There is no clinically meaningful effect of age (18 years and older), race, or gender on the pharmacokinetics of raltegravir.

Hepatic Impairment

Raltegravir is eliminated primarily by glucuronidation in the liver. The pharmacokinetics of a single 400-mg dose of raltegravir were not altered in patients with moderate (Child-Pugh Score 7 to 9) hepatic impairment.

No hepatic impairment study has been conducted with ISENTRESS HD 1200 mg (2 × 600 mg) once daily.The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.

Renal Impairment

Renal clearance of unchanged drug is a minor pathway of elimination. The pharmacokinetics of a single 400-mg dose of raltegravir were not altered in patients with severe (24-hour creatinine clearance of <30 mL/min/1.73 m 2) renal impairment.

No renal impairment study was conducted with ISENTRESS HD 1200 mg (2 × 600 mg) once daily.

The extent to which ISENTRESS may be dialyzable is unknown.

Drug Interactions

In vitro , raltegravir does not inhibit (IC50>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A. In vivo , raltegravir does not inhibit CYP3A4. Moreover, in vitro , raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Similarly, raltegravir is not an inhibitor (IC50>50 µM) of UGT1A1 or UGT2B7, and raltegravir does not inhibit P-glycoprotein-mediated transport.

Raltegravir drug interaction study results are shown in Tables 16 and 17. For information regarding clinical recommendations [see Drug Interactions (7)].

Table 16: Effect of Other Agents on the Pharmacokinetics of Raltegravir in Adults
Coadministered Drug Coadministered Drug Dose/Schedule Raltegravir Dose/Schedule Ratio (90% Confidence Interval) of Raltegravir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00
n C max AUC C min
*
Study conducted in HIV-infected subjects.
aluminum and magnesium hydroxide antacid * 20 mL single dose given with raltegravir 400 mg twice daily 25 0.56 (0.42, 0.73) 0.51 (0.40, 0.65) 0.37 (0.29, 0.48)
20 mL single dose given 2 hours before raltegravir 23 0.49 (0.33, 0.71) 0.49 (0.35, 0.67) 0.44 (0.34, 0.55)
20 mL single dose given 2 hours after raltegravir 23 0.78 (0.53, 1.13) 0.70 (0.50, 0.96) 0.43 (0.34, 0.55)
20 mL single dose given 4 hours before raltegravir 17 0.78 (0.55, 1.10) 0.81 (0.63, 1.05) 0.40 (0.31, 0.52)
20 mL single dose given 4 hours after raltegravir 18 0.70 (0.48, 1.04) 0.68 (0.50, 0.92) 0.38 (0.30, 0.49)
20 mL single dose given 6 hours before raltegravir 16 0.90 (0.58, 1.40) 0.87 (0.64, 1.18) 0.50 (0.39, 0.65)
20 mL single dose given 6 hours after raltegravir 16 0.90 (0.58, 1.41) 0.89 (0.64, 1.22) 0.51 (0.40, 0.64)
aluminum and magnesium hydroxide antacid * 20 mL single dose given 12 hours after raltegravir 1200 mg single dose 19 0.86 (0.65, 1.15) 0.86 (0.73, 1.03) 0.42 (0.34, 0.52)
atazanavir 400 mg daily 100 mg single dose 10 1.53 (1.11, 2.12) 1.72 (1.47, 2.02) 1.95 (1.30, 2.92)
atazanavir 400 mg daily 1200 mg single dose 14 1.16 (1.01, 1.33) 1.67 (1.34, 2.10) 1.26 (1.08, 1.46)
atazanavir/ritonavir 300 mg/100 mg daily 400 mg twice daily 10 1.24 (0.87, 1.77) 1.41 (1.12, 1.78) 1.77 (1.39, 2.25)
boceprevir 800 mg three times daily 400 mg single dose 22 1.11 (0.91-1.36) 1.04 (0.88-1.22) 0.75 (0.45-1.23)
calcium carbonate antacid * 3000 mg single dose given with raltegravir 400 mg twice daily 24 0.48 (0.36, 0.63) 0.45 (0.35, 0.57) 0.68 (0.53, 0.87)
calcium carbonate antacid * 3000 mg single dose given with raltegravir 1200 mg single dose 19 0.26 (0.21, 0.32) 0.28 (0.24, 0.32) 0.52 (0.45, 0.61)
3000 mg single dose given 12 hours after raltegravir 0.98 (0.81, 1.17) 0.90 (0.80, 1.03) 0.43 (0.36, 0.51)
efavirenz 600 mg daily 400 mg single dose 9 0.64 (0.41, 0.98) 0.64 (0.52, 0.80) 0.79 (0.49, 1.28)
efavirenz 600 mg daily 1200 mg single dose 21 0.91 (0.70, 1.17) 0.86 (0.73, 1.01) 0.94 (0.76, 1.17)
etravirine 200 mg twice daily 400 mg twice daily 19 0.89 (0.68, 1.15) 0.90 (0.68, 1.18) 0.66 (0.34, 1.26)
omeprazole * 20 mg daily 400 mg twice daily 18 1.51 (0.98, 2.35) 1.37 (0.99, 1.89) 1.24 (0.95, 1.62)
rifampin 600 mg daily 400 mg single dose 9 0.62 (0.37, 1.04) 0.60 (0.39, 0.91) 0.39 (0.30, 0.51)
rifampin 600 mg daily 400 mg twice daily when administered alone; 800 mg twice daily when administered with rifampin 14 1.62 (1.12, 2.33) 1.27 (0.94, 1.71) 0.47 (0.36, 0.61)
ritonavir 100 mg twice daily 400 mg single dose 10 0.76 (0.55, 1.04) 0.84 (0.70, 1.01) 0.99 (0.70, 1.40)
tenofovir disoproxil fumarate 300 mg daily 400 mg twice daily 9 1.64 (1.16, 2.32) 1.49 (1.15, 1.94) 1.03 (0.73, 1.45)
tipranavir/ritonavir 500 mg/200 mg twice daily 400 mg twice daily 15 (14 for C min ) 0.82 (0.46, 1.46) 0.76 (0.49, 1.19) 0.45 (0.31, 0.66)
Table 17: Effect of Raltegravir on the Pharmacokinetics of Other Agents in Adults
Substrate Drug Raltegravir Dose/Schedule Ratio (90% Confidence Interval) of Substrate Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00
n C max AUC C min
Tenofovir disoproxil fumarate 300 mg 400 mg 9 0.77 (0.69, 0.85) 0.90 (0.82, 0.99) C24hr 0.87 (0.74, 1.02)
Etravirine 200 mg 400 mg 19 1.04 (0.97, 1.12) 1.10 (1.03, 1.16) 1.17 (1.10, 1.26)

In drug interaction studies, there was no effect of raltegravir on the PK of ethinyl estradiol, methadone, midazolam or boceprevir.

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