Pharmacological classification: A 20.2.8 Antiviral agent.
Lopinavir provides the antiviral activity of RILOVIA 100/25 and RILOVIA 200/50 tablets. Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.
The in vitro antiviral activity of lopinavir against laboratory and clinical HIV strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean IC50 of lopinavir against five different HIV-1 laboratory strains ranged from 10-27 nM. In the presence of 50% human serum, the mean IC50 of lopinavir against these live laboratory strains ranged from 68-289 nM.
HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro. HIV-1 has been passaged in vitro with lopinavir alone and with lopinavir plus ritonavir at concentration ratios representing the range of plasma concentration ratios observed during lopinavir and ritonavir therapy. Genotypic and phenotypic analysis of viruses selected in these passages suggests that the presence of ritonavir, at these concentration ratios, does not measurably influence the selection of lopinavirresistant viruses.
Activity of other protease inhibitors against isolates that developed incremental resistance to lopinavir after lopinavir/ritonavir tablets therapy in protease inhibitor experienced patients: The presence of cross-resistance to other protease inhibitors was analysed in 18 rebound isolates that had demonstrated evolution of resistance to lopinavir during 3 Phase II and one Phase III studies of lopinavir/ritonavir tablets in protease inhibitor-experienced patients. The median fold IC50 of lopinavir for these 18 isolates at baseline and rebound was 6,9- and 63-fold, respectively, compared to wild type virus. In general, rebound isolates either retained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir, saquinavir and atazanavir. Modest decreases in amprenavir activity were noted with a median increase of IC50 from 3,7- to 8-fold in the baseline and rebound isolates, respectively. Isolates retained susceptibility to tipranavir with a median increase of IC50 in baseline and rebound isolates of 1,9- and 1,8–fold, respectively, compared to wild type virus.
The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolised by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of lopinavir/ritonavir tablets 400/100 mg twice daily yielded mean steady-state lopinavir plasma concentrations 15 to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of lopinavir/ritonavir tablets is due to lopinavir.
Multiple dosing with 400/100 mg lopinavir/ritonavir tablets twice daily for 3 to 4 weeks and without meal restriction produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 9,6 ± 4,4 μg/ml, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 5,5 ± 4,0 μg/ml. Lopinavir AUC over a 12 hour dosing interval averaged 82,8 ± 44,5 μg•h/ml. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established.
Administration of a single 400/100 mg dose of lopinavir/ritonavir tablets under fed conditions (high fat, 872 kcal, 56% from fat) compared to fasted state was associated with no significant changes in Cmax and AUCinf. Therefore, lopinavir/ritonavir tablets may be taken with or without food.
At steady state, lopinavir is approximately 98-99% bound to serum proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg lopinavir/ritonavir tablets twice daily, and is similar between healthy volunteers and HIV-positive patients.
In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir and therefore, increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg lopinavir/ritonavir tablets dose was due to parent substance. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 to 16 days.
After a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10,4 ± 2,3% and 82,6 ± 2,5% of an administered dose of 14C-lopinavir can be accounted for in urine and faeces, respectively, after 8 days. Unchanged lopinavir accounted for approximately 2,2% and 19,8% of the administered dose in urine and faeces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The effective (peak to trough) half-life of lopinavir over a 12 hour dosing interval averaged 5-6 hours, and the apparent clearance (CL/F) of lopinavir is 6 to 7 l/h.
QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper limit) differences in QTcF from placebo were 3,6 (6,3) and 13,1(15,8) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily LPV/r, respectively. The induced QRS interval prolongation from 6 ms to 9,5 ms with high dose lopinavir/ritonavir (800/200 mg twice daily) contributes to QT prolongation. The two regimens resulted in exposures on Day 3 which were approximately 1,5 and 3-fold higher than those observed with recommended once daily or twice daily LPV/r doses at steady state. No subject experienced an increase in QTcF of ≥60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.
Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ritonavir in the same study on Day 3. The mean changes from baseline in PR interval ranged from 11,6 ms to 24,4 ms in the 12 hour interval post dose. Maximum PR interval was 286 msec and no second or third degree heart block was observed.
There are limited pharmacokinetic data in children below 2 years of age. The pharmacokinetics of lopinavir/ritonavir oral solution 300/75 mg/m² twice daily and 230/57,5 mg/m² twice daily have been studied in a total of 53 paediatric patients, ranging in age from 6 months to 12 years. The lopinavir mean steady state AUC, Cmax, and Cmin were 72,6 ± 31,1 μg•h/ml, 8,2 ± 2,9 μg/ml and 3,4 ± 2,1 μg/ml, respectively after lopinavir/ritonavir oral solution 230/57,5 mg/m² twice daily without nevirapine (n=12), and were 85,8 ± 36,9 μg•h/ml, 10,0 ± 3,3 μg/ml and 3,6 ± 3,5 μg/ml, respectively after 300/75 mg/m² twice daily with nevirapine (n=12). The 230/57,5 mg/m² twice daily regimen without nevirapine and the 300/75 mg/m² twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen without nevirapine.
Lopinavir/ritonavir tablets pharmacokinetics have not been studied in the elderly. No age or gender related pharmacokinetic differences have been observed in adult patients.
Lopinavir/ritonavir tablets pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.
The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to moderate hepatic impairment were compared with those of HIV-infected patients with normal hepatic function in a multiple dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited increase in total lopinavir concentrations of approximately 30% and 20% in Cmax has been observed.
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