Ritonavir clinical pharmacology: Difference between revisions
(Created page with "__NOTOC__ {{Ritonavir }} {{CMG}}; {{AE}} {{chetan}} <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = NORVIR (RITONAVIR) CAPSULE [ABBVIE INC.] | ur...") |
No edit summary |
||
| Line 3: | Line 3: | ||
{{CMG}}; {{AE}} {{chetan}} | {{CMG}}; {{AE}} {{chetan}} | ||
==Clinical Pharmacology== | |||
===Mechanism of Action=== | |||
Ritonavir is an antiviral drug [see Microbiology ]. | |||
===Pharmacokinetics=== | |||
The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-1 infected patients (CD4 greater than or equal to 50 cells per µL). See Table 5 for ritonavir pharmacokinetic characteristics. | |||
===Absorption=== | |||
The absolute bioavailability of ritonavir has not been determined. | |||
===Effect of Food on Oral Absorption=== | |||
After a single 600 mg dose under non-fasting conditions, in two separate studies, the soft gelatin capsule (n = 57) formulation yielded a mean ± SD area under the plasma concentration-time curve (AUC) of 121.7 ± 53.8. Relative to fasting conditions, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate). | |||
===Metabolism=== | |||
Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The[[ isopropylthiazole]] oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver [[microsomes]] have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M-2. | |||
===Elimination=== | |||
In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance. | |||
{| | |||
|- | |||
| [[File:|800px|thumb]] | |||
|- | |||
|} | |||
===Effects on Electrocardiogram=== | |||
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state. | |||
PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir [see Warnings and Precautions (5.5)]. | |||
===Special Populations=== | |||
====Gender, Race and Age==== | |||
No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients. | |||
A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified. | |||
====Pediatric Patients==== | |||
Steady-state pharmacokinetics were evaluated in 37 HIV-1 infected patients ages 2 to 14 years receiving doses ranging from 250 mg per m2 twice-daily to 400 mg per m2 twice-daily in PACTG Study 310, and in 41 HIV-1 infected patients ages 1 month to 2 years at doses of 350 and 450 mg per m2 twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL per F per m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m2 twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m2 twice-daily in children less than 2 years of age. Higher ritonavir exposures were not evident with 450 mg per m2 twice-daily compared to the 350 mg per m2 twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration-time curve and trough concentrations obtained after administration with 350 or 450 mg per m2 twice-daily in children less than 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice-daily. | |||
====Renal Impairment==== | |||
Ritonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment. | |||
====Hepatic Impairment==== | |||
Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment. | |||
===Drug Interactions=== | |||
[see also Contraindications , Warnings and Precautions , and Drug Interactions] | |||
Table 6 and Table 7 summarize the effects on AUC and Cmax, with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see Table 4 in Drug Interactions .<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = NORVIR (RITONAVIR) CAPSULE [ABBVIE INC.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=13b059c6-0c6c-49a5-b985-a4b05caf9ac9 | publisher = | date = | accessdate = }}</ref> | |||
{| | |||
|- | |||
| [[File:|800px|thumb]] | |||
|- | |||
|} | |||
{| | |||
|- | |||
| [[File:|800px|thumb]] | |||
|- | |||
|} | |||
{| | |||
|- | |||
| [[File:|800px|thumb]] | |||
|- | |||
|} | |||
{| | |||
|- | |||
| [[File:|800px|thumb]] | |||
|- | |||
|} | |||
==References== | ==References== | ||
Latest revision as of 17:28, 9 January 2014
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
Clinical Pharmacology
Mechanism of Action
Ritonavir is an antiviral drug [see Microbiology ].
Pharmacokinetics
The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-1 infected patients (CD4 greater than or equal to 50 cells per µL). See Table 5 for ritonavir pharmacokinetic characteristics.
Absorption
The absolute bioavailability of ritonavir has not been determined.
Effect of Food on Oral Absorption
After a single 600 mg dose under non-fasting conditions, in two separate studies, the soft gelatin capsule (n = 57) formulation yielded a mean ± SD area under the plasma concentration-time curve (AUC) of 121.7 ± 53.8. Relative to fasting conditions, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate).
Metabolism
Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. Theisopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M-2.
Elimination
In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.
| [[File:|800px|thumb]] |
Effects on Electrocardiogram
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state.
PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir [see Warnings and Precautions (5.5)].
Special Populations
Gender, Race and Age
No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.
A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.
Pediatric Patients
Steady-state pharmacokinetics were evaluated in 37 HIV-1 infected patients ages 2 to 14 years receiving doses ranging from 250 mg per m2 twice-daily to 400 mg per m2 twice-daily in PACTG Study 310, and in 41 HIV-1 infected patients ages 1 month to 2 years at doses of 350 and 450 mg per m2 twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL per F per m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m2 twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m2 twice-daily in children less than 2 years of age. Higher ritonavir exposures were not evident with 450 mg per m2 twice-daily compared to the 350 mg per m2 twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration-time curve and trough concentrations obtained after administration with 350 or 450 mg per m2 twice-daily in children less than 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice-daily.
Renal Impairment
Ritonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment.
Hepatic Impairment
Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.
Drug Interactions
[see also Contraindications , Warnings and Precautions , and Drug Interactions]
Table 6 and Table 7 summarize the effects on AUC and Cmax, with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see Table 4 in Drug Interactions .[1]
| [[File:|800px|thumb]] |
| [[File:|800px|thumb]] |
| [[File:|800px|thumb]] |
| [[File:|800px|thumb]] |
References
Adapted from the FDA Package Insert.