The effects of other drugs on the pharmacokinetics of ritonavir
Drugs that increase activity CYP3A, such as phenobarbital, carbamazepine, dexamethasone, phenytoin, rifampicin and rifabutin, lead to an increase in the clearance of ritonavir, as a result of which its concentration in the blood plasma decreases.
Rifampicin leads to a decrease AUC and FROMmOh ritonavir, while clarithromycin and fluconazole increase the values of these parameters, and didanosine and zidovudine do not affect them. Fluoxetine enhances AUC ritonavir, but does not affect its FROMmOh.
Smoking of tobacco leads to a decrease AUC ritonavir by 18%.
The effect of ritonavir on the pharmacokinetics of other drugs
Ritonavir is an isoenzyme inhibitor CYP3A cytochrome P450, resulting in the simultaneous administration of ritonavir with drugs metabolized predominantly with the participation of isoenzyme CYP3A, it is possible to increase their concentration in plasma (more than 3 times). The use of ritonavir with drugs, increasing concentrations in the plasma can lead to potentially serious and / or life-threatening conditions is contraindicated. The use of ritonavir with other isoenzyme substrates CYP3A may require dose adjustment and careful monitoring of patients. Less ritonavir inhibits isoenzyme CYP2D6. With simultaneous administration of ritonavir and isoenzyme substrates CYP2D6 it is possible to increase the concentration of the latter in plasma (2 times), which may require correction of their dose in the direction of decrease. Ritonavirprobably is an inducer of isoenzymes CYP3A, CYP1A2, CYP2C9, CYP2C19 and CYP2B6, as well as a number of other enzymes, including glucuronosyltransferase, which may require an increase in the dose of preparations biotransforming under the action of this enzyme, due to a decrease in their effectiveness in joint admission.
There are reports of the development of adverse reactions from the cardiovascular and nervous systems with the simultaneous use of ritonavir with disopyramide, mexiletine, nefazodone or fluoxetine.
Alprazolam: statistically significantly decreases FROMmOh alprazolam (16%) and its sedative effect when taken concomitantly with ritonavir. There may also be minor psychomotor abnormalities.
Amprenavir: the concentration rises.
Boszentan: simultaneous reception of ritonavir and bosentan leads to a significant increase in the level of bosentan. In patients who received ritonavir for at least 10 days, the initial dose of bosentan is 62.5 mg once a day or every other day, depending on individual tolerability. Patients who receive bosentan, it is necessary to stop receiving it, at least 36 hours before the start of ritonavir.10 days after the initiation of ritonavir, it is possible to resume bosentan at an initial dose of 62.5 mg once a day or every other day, depending on individual tolerability.
Buspirone: primarily metabolized with the participation of isoenzyme CYP3A4, therefore its concentration can be significantly increased, as a result of which it is recommended to reduce the dose of buspirone on the background of its reception with ritonavir.
Warfarin: the concentration of warfarin may change when it is used together with ritonavir - it is recommended to monitor the clotting characteristics of the blood.
Vinblastine, vincristine: when used simultaneously with ritonavir, serum concentrations of these drugs increase, which potentiates an increase in the associated adverse reactions.
Voriconazole: simultaneous application of ritonavir to 400 mg every 12 hours reduces AUC voriconazole in the equilibrium state on average by 82%, which dramatically reduces its effectiveness, so the joint use of these drugs is not recommended.
Delavirdine: inhibitor of the isoenzyme SURDA4-metabolized drugs.
Increases equilibrium FROMmOh and AUC ritonavir by 50% and 75%, respectively, as a result of which a reduction in the dose of ritonavir is required. In its turn ritonavir does not affect the pharmacokinetics of delavirdine.
Desipramine: ritonavir increases by 145% AUC desipramine, therefore, a dose reduction of desipramine should be provided for patients taking it in combination with ritonavir.
Didanosine: ritonavir lowers the equilibrium FROMmOh and AUC didanosine by 16% and 13%, respectively. To avoid incompatibility, it is recommended to use drugs with an interval of not less than 2.5 hours.
Digoxin: simultaneous reception of ritonavir (300 mg every 12 hours) and digoxin leads to a significant increase in the level of digoxin. With the simultaneous use of digoxin and ritonavir, caution should be exercised, with adequate monitoring of the level of digoxin in the plasma.
Preparations St. John's wort perfumed (Hypericum perforatum): should not be taken in conjunction with ritonavir, since the concentration of ritonavir in the plasma is lowered due to induction of the isoenzyme CYP3A4. As a result, therapeutic effectiveness is reduced and resistance to ritonavir develops.
Zidovudine: ritonavir reduced FROMmOh and AUC zidovudine by approximately 27% and 25%, respectively. Changes in the dose of zidovudine when used with ritonavir is not required.
Indinavir: ritonavir inhibits the metabolism of indinavir, which occurs with the participation of isoenzyme CYP3A, and leads to an increase in the concentration of indinavir in plasma.
The risk of nephrolithiasis may increase when ritonavir is combined with indinavir at doses equal to or greater than 800 mg twice daily. It is necessary to maintain adequate hydration of patients and monitor their condition.
Ketoconazole: the use of ritonavir in combination with ketoconazole (200 mg / day) was expressed in a marked increase in the levels of ketoconazole in plasma: medium AUC0-24 increased by 244% and FROMmOh - by 55%. The mean half-life of ketoconazole increased from 2.7 to 13.2 hours. Mean values AUC0-24 and FROMmOh ritonavir increased by 18% and 10%, respectively. Doses of ritonavir do not need to be corrected with simultaneous admission with ketoconazole, while doses of ketoconazole 200 mg / day or higher should not be used in combination with ritonavir. It is recommended to reduce the dose of ketoconazole.
Clarithromycin: metabolism is significantly inhibited, resulting in FROMmOh clarithromycin is increased by 31%, Cmin - by 182%, AUC - by 77%. Almost completely inhibited the formation of 14-hydroxyclarithromycin (the main metabolite of clarithromycin).
Due to the large therapeutic range of clarithromycin, there is no need to reduce the dose in patients with normal renal function. For patients with renal insufficiency correction should provide the following doses: the creatinine clearance (CC) of 30 to 60 ml / min clarithromycin dose should be reduced by 50%, with creatinine clearance <30 mL / min clarithromycin dose should be reduced by 75%. Doses of clarithromycin> 1 g / day should not be given in combination with ritonavir.
Methadone: The use of ritonavir in combination with methadone caused a decrease in the concentration of methadone. It may be necessary to increase the dose of methadone when applied in combination with ritonavir.
Nelfinavir: the interaction between ritonavir and nelfinavir probably occurs with both inhibition and induction of cytochrome P450. Simultaneously with a significant increase in the concentration of M8 (the main active metabolite of nelfinavir), the concentration of nelfinavir itself increases to a lesser extent.
Contraceptive preparations for oral or in the form of a patch: The use of ritonavir in combination with combined forms of ethinyl estradiol for oral administration was expressed in a decrease in the mean AUC ethinyl estradiol by 32%, and its FROMmOh - by 40%. Contraceptive drugs with a higher concentration of ethinylestradiol should be used or alternative methods of contraception should be used.
Rifabutin: The use in combination with ritonavir leads to a multiple (4 to 35 times) increase AUC and FROMmOh rifabutin and its active metabolite 25-O-deacetyl rifabutin, which has clinical consequences. It is recommended to reduce the dose of rifabutin by at least 3/4 of the usual daily dose of 300 mg (ie, 150 mg every other day or 3 times a week). If necessary, further reduction of the dose is recommended.
Saquinavir: data from pharmacokinetic studies in patients indicate that its use in combination with ritonavir causes a multiple increase in the concentration of saquinavir in the blood (AUC, A 17-fold increase). Long-term combination therapy at doses of more than 400 mg twice a day of each drug was accompanied by an increase in the frequency of adverse reactions. Do not assign saquinavir and ritonavir together with rifampicin because of the risk of severe hepatotoxicity when using these three drugs at the same time.
Salmeterol: with the simultaneous administration of salmeterol with ritonavir, an increase in the concentration of salmeterol is noted. The joint administration of ritonavir with salmeterol is not recommended due to an increased risk of salmeterol side effects, including lengthening of the interval QT, palpitation and tachycardia.
Means for the treatment of erectile dysfunction
Sildenafil: it is recommended to use caution sildenafil in patients taking ritonavir. The use of sildenafil in combination with ritonavir causes a significant (11-fold) increase AUC sildenafil in the plasma, which increases the risk of adverse reactions associated with sildenafil, such as lowering blood pressure, fainting, blurred vision, and prolonged erections.
Tadalafil: should be used tadalafil with caution in reduced doses - not more than 10 mg every 72 hours with enhanced monitoring of adverse events.
Vardenafil: should use vardenafil with caution in reduced doses - no more than 2.5 mg every 72 hours with enhanced monitoring of adverse events.
Combination of sulfamethoxazole / trimethoprim: The use of ritonavir in combination with sulfamethoxazole / trimethoprim caused a 20% reduction AUC sulfamethoxazole and a 20% increase AUC trimethoprim. Correction of the dose of sulfamethoxazole / trimethoprim when used in combination with ritonavir is usually not required.
Theophylline: may require an increase in the dose of theophylline, since the use in combination with ritonavir caused a decrease AUC theophylline by 43%.
Trazodone: At the same time, the use of ritonavir and trazodone may increase trazodone concentrations. There were observed such undesirable phenomena as nausea, dizziness, lowering of arterial pressure, fainting. Care should be taken when using trazodone and ritonavir concurrently, a dose reduction of trazodone may be required.
Fluticasone propionate: taking ritonavir and fluticasone propionate leads to an increase in the concentration of fluticasone propionate.
Fusidic acid: It is assumed,that the use of ritonavir in combination with fusidic acid increases the concentration of both fusidic acid and ritonavir, as a protease inhibitor in plasma.
Efavirenz: equilibrium AUC efavirenz increased by 21%. There was a related 17% increase AUC ritonavir.
The effect of ritonavir on the pharmacokinetics of other drugs with simultaneous application
Ritonavir leads to a significant increase AUC (more than 3 times) of the following drugs: alfetanil, amlodipine, amiodarone, amprenavir, atazanavir, atorvastatin, bromocriptine, buspirone, vardenafil, verapamil, darunavir, dexamethasone, diltiazem, indinavir, isradipine, itraconazole, carbamazepine, ketoconazole, lidocaine, lovastatin, loratadine, miconazole, nefazodone, nicardipine, nimodipine, nisoldipine, nitrendipine, nifedipine, rifabutin, saquinavir, sertraline, sildenafil, simvastatin, sirolimus, tadalafil, tacrolimus, tamoxifen, tipranavir, felodipine, fentanyl, fluticasone, fusidic acid, quinine, ciclosporin, everolimus, erythromycin.
Ritonavir leads to a moderate increase AUC (in 1,5-3 times) preparations: amitriptyline, bupropion, venlafaxine, vinblastine, vincristine, haloperidol, hydrocodone, desipramine, dexfenfluramine, diazepam, disopyramide, dronabinol, zolpidem, imipramine, clarithromycin, clomipramine, clonazepam, the clorazepate dipotassium, maprotiline, mexiletine, methamphetamine, metoprolol, nortriptyline, oxycodone, ondansetron, paclitaxel, paroxetine, penbutolol, perphenazine, pindolol, prednisolone, dextropropoxyphene, risperidone, thioridazine, trazodone, tramadol, trimipramine, fluoxetine, flurazepam, chlorpromazine, estazolam, etoposide, ethosuximide.
Ritonavir leads to a moderate increase or decrease AUC preparations: glyburide, glimepride, glipizide, diclofenac, ibuprofen, indomethacin, ifosfamide, lansoprazole, losartan, omeprazole, piroxicam, proguanil, propranolol, tolbutamide, flurbiprofen, cyclophosphamide.
When used simultaneously with ritonavir, a reduction AUC preparations: atovahon, hydromorphone, valproate semiotria, diphenoxylate, ketoprofen, ketorolac, clozapine, clofibrate, codeine, lamotrigine, loperamide, lorazepam, pethidine, methadone, metoclopramide, morphine, naproxen, oxazepam, propofol, temazepam, theophylline, phenytoin, ethinyl estradiol.