Kaletra (Page 7 of 11)
12.3 Pharmacokinetics
The pharmacokinetic properties of lopinavir are summarized in Table 13. The steady-state pharmacokinetic parameters of lopinavir are summarized in Table 14. Under fed conditions, lopinavir concentrations were similar following administration of KALETRA tablets to capsules with less pharmacokinetic variability. Under fed conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA capsules and oral solution.
| Absorption | |
| T max (hr) a | 4.4 ± 0.8 |
| Effect of meal (relative to fasting) Tablet Oral solution | ↑ 19% b ↑ 130% b |
| Distribution | |
| % Bound to human plasma proteins | > 98 |
| V d /F a (L) | 16.9 |
| Metabolism | |
| Metabolism | CYP3A |
| Elimination | |
| Major route of elimination | hepatic |
| t 1/2 (h) a | 6.9 ± 2.2 |
| % of dose excreted in urine | 10.4 ± 2.3 |
| % of dose excreted in feces | 82.6 ± 2.5 |
| a. Kaletra tablet b. Changes in AUC values | |
| Pharmacokinetic Parameter | Twice Daily a | Once Daily b |
| C max (µg/mL) | 9.8 ± 3.7 | 11.8 ± 3.7 |
| C min (µg/mL) | 5.5 ± 2.7 | 1.7 ± 1.6 |
| AUC tau (µg•h/mL) | 92.6 ± 36.7 | 154.1 ± 61.4 |
| ||
No gender or race related pharmacokinetic differences have been observed in adult patients. Lopinavir pharmacokinetics have not been studied in elderly patients.
The 230/57.5 mg/m 2 twice daily regimen without nevirapine and the 300/75 mg/m 2 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.
| C max (μg/mL) | C min (μg/mL) | AUC 12 (μg•hr/m ) |
| Age ≥ 14 Days to < 6 Weeks Cohort (N = 9): | ||
| 5.17 ± 1.84 a | 1.40 ± 0.48 a | 43.39 ± 14.80 a |
| Age ≥ 6 Weeks to < 6 Months Cohort (N = 18): | ||
| 9.39 ± 4.91 a | 1.95 ± 1.80 a | 74.50 ± 37.87 a |
| Age ≥ 6 Months to ≤ 12 years Cohort (N = 24): | ||
| 8.2 ± 2.9 b | 3.4 ± 2.1 b | 72.6 ± 31.1 b |
| 10.0 ± 3.3 c | 3.6 ± 3.5 c | 85.8 ± 36.9 c |
| ||
The C 12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum in 12 HIV-infected pregnant women received KALETRA 400 mg/100 mg twice daily. Yet this decrease is not considered clinically relevant in patients with no documented KALETRA-associated resistance substitutions receiving 400 mg/100 mg twice daily [see Use in Specific Populations ( 8.1)] .
Lopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.
Multiple dosing of KALETRA 400/100 mg twice daily to HIV-1 and HCV co-infected patients with mild to moderate hepatic impairment (n = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in C max compared to HIV-1 infected subjects with normal hepatic function (n = 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). KALETRA has not been studied in patients with severe hepatic impairment [see Warnings and Precautions ( 5.4) and Use in Specific Populations ( 8.6)] .
KALETRA is an inhibitor of the P450 isoform CYP3A in vitro. KALETRA does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.
KALETRA has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation.
The effects of co-administration of KALETRA on the AUC, C max and C min are summarized in Table 16 (effect of other drugs on lopinavir) and Table 17 (effect of KALETRA on other drugs). For information regarding clinical recommendations, see Table 12 in Drug Interactions ( 7) .
| Co- administered Drug | Dose of Co- administered Drug (mg) | Dose of KALETRA (mg) | n | Ratio (in combination with Co-administered drug/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | ||
| C max | AUC | C min | ||||
| Efavirenz 1 | 600 at bedtime | 400/100 capsule twice daily | 11, 7 3 | 0.97 (0.78, 1.22) | 0.81 (0.64, 1.03) | 0.61 (0.38, 0.97) |
| 600 at bedtime | 500/125 tablet twice daily | 19 | 1.12 (1.02, 1.23) | 1.06 (0.96, 1.17) | 0.90 (0.78, 1.04) | |
| 600 at bedtime | 600/150 tablet twice daily | 23 | 1.36 (1.28, 1.44) | 1.36 (1.28, 1.44) | 1.32 (1.21, 1.44) | |
| Etravirine | 200 twice daily | 400/100 mg twice day (tablets) | 16 | 0.89 (0.82-0.96) | 0.87 (0.83-0.92) | 0.80 (0.73-0.88) |
| Fosamprenavir 2 | 700 twice daily plus ritonavir 100 twice daily | 400/100 capsule twice daily | 18 | 1.30 (0.85, 1.47) | 1.37 (0.80, 1.55) | 1.52 (0.72, 1.82) |
| Ketoconazole | 200 single dose | 400/100 capsule twice daily | 12 | 0.89 (0.80, 0.99) | 0.87 (0.75, 1.00) | 0.75 (0.55, 1.00) |
| Nelfinavir | 1000 twice daily | 400/100 capsule twice daily | 13 | 0.79 (0.70, 0.89) | 0.73 (0.63, 0.85) | 0.62 (0.49, 0.78) |
| Nevirapine | 200 twice daily steady-state | 400/100 capsule twice daily | 22, 19 3 | 0.81 (0.62, 1.05) | 0.73 (0.53, 0.98) | 0.49 (0.28, 0.74) |
| 7 mg/kg or 4 mg/kg once daily; twice daily 1 wk 5 | (> 1 yr) 300/ 75 mg/m 2 oral solution twice daily | 12, 15 3 | 0.86 (0.64, 1.16) | 0.78 (0.56, 1.09) | 0.45 (0.25, 0.81) | |
| Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir 2 | 25/150/100 + dasabuvir 400 | 400/100 tablet twice daily | 6 | 0.87 (0.76, 0.99) | 0.94 (0.81, 1.10) | 1.15 (0.93, 1.42) |
| Omeprazole | 40 once daily, 5 d | 400/100 tablet twice daily, 10 d | 12 | 1.08 (0.99, 1.17) | 1.07 (0.99, 1.15) | 1.03 (0.90, 1.18) |
| 40 once daily, 5 d | 800/200 tablet once daily, 10 d | 12 | 0.94 (0.88, 1.00) | 0.92 (0.86, 0.99) | 0.71 (0.57, 0.89) | |
| Pravastatin | 20 once daily, 4 d | 400/100 capsule twice daily, 14 d | 12 | 0.98 (0.89, 1.08) | 0.95 (0.85, 1.05) | 0.88 (0.77, 1.02) |
| Ranitidine | 150 single dose | 400/100 tablet twice daily, 10 d | 12 | 0.99 (0.95, 1.03) | 0.97 (0.93, 1.01) | 0.90 (0.85, 0.95) |
| 150 single dose | 800/200 tablet once daily, 10 d | 10 | 0.97 (0.95, 1.00) | 0.95 (0.91, 0.99) | 0.82 (0.74, 0.91) | |
| Rifabutin | 150 once daily | 400/100 capsule twice daily | 14 | 1.08 (0.97, 1.19) | 1.17 (1.04, 1.31) | 1.20 (0.96, 1.65) |
| Rifampin | 600 once daily | 400/100 capsule twice daily | 22 | 0.45 (0.40, 0.51) | 0.25 (0.21, 0.29) | 0.01 (0.01, 0.02) |
| 600 once daily | 800/200 capsule twice daily | 10 | 1.02 (0.85, 1.23) | 0.84 (0.64, 1.10) | 0.43 (0.19, 0.96) | |
| 600 once daily | 400/400 capsule twice daily | 9 | 0.93 (0.81, 1.07) | 0.98 (0.81, 1.17) | 1.03 (0.68, 1.56) | |
| Rilpivirine | 150 once daily | 400/100 twice daily (capsules) | 15 | 0.96 (0.88-1.05) | 0.99 (0.89-1.10) | 0.89 (0.73-1.08) |
| Ritonavir | 100 twice daily | 400/100 capsule twice daily | 8, 21 3 | 1.28 (0.94, 1.76) | 1.46 (1.04, 2.06) | 2.16 (1.29, 3.62) |
| Tipranavir/ ritonavir | 500/200 twice daily | 400/100 capsule twice daily | 21 69 3 | 0.53 (0.40, 0.69) | 0.45 (0.32, 0.63) | 0.30 (0.17, 0.51) 0.48 4 (0.40, 0.58) |
| 1 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. 2 Data extracted from the U.S. prescribing information of co-administered drugs. 3 Parallel group design 4 Drug levels obtained at 8-16 hours post dose N/A = Not available. | ||||||
| Co- administered Drug | Dose of Co- administered Drug (mg) | Dose of KALETRA (mg) | n | Ratio (in combination with KALETRA/alone) of Co- administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | ||
| C max | AUC | C min | ||||
| Bedaquiline 1 | 400 single dose | 400/100 twice daily | N/A | N/A | 1.22 (1.11, 1.34) | N/A |
| Efavirenz | 600 at bedtime | 400/100 capsule twice daily | 11, 12 3 | 0.91 (0.72, 1.15) | 0.84 (0.62, 1.15) | 0.84 (0.58, 1.20) |
| Elbasvir/ grazoprevir 1 | 50 once daily | 400/100 twice daily | 10 | 2.87 (2.29, 3.58) | 3.71 (3.05, 4.53) | 4.58 (3.72, 5.64) |
| 200 once daily | 13 | 7.31 (5.65, 9.45) | 12.86 (10.25, 16.13) | 21.70 (12.99, 36.25) | ||
| Ethinyl Estradiol | 35 µg once daily (Ortho Novum ®) | 400/100 capsule twice daily | 12 | 0.59 (0.52, 0.66) | 0.58 (0.54, 0.62) | 0.42 (0.36, 0.49) |
| Etravirine | 200 twice daily | 400/100 tablet twice day | 16 | 0.70 (0.64-0.78) | 0.65 (0.59-0.71) | 0.55 (0.49-0.62) |
| Fosamprenavir 1 | 700 twice daily plus ritonavir 100 twice daily | 400/100 capsule twice daily | 18 | 0.42 (0.30, 0.58) | 0.37 (0.28, 0.49) | 0.35 (0.27, 0.46) |
| Indinavir | 600 twice daily combo nonfasting vs. 800 three times daily alone fasting | 400/100 capsule twice daily | 13 | 0.71 (0.63, 0.81) | 0.91 (0.75, 1.10) | 3.47 (2.60, 4.64) |
| Ketoconazole | 200 single dose | 400/100 capsule twice daily | 12 | 1.13 (0.91, 1.40) | 3.04 (2.44, 3.79) | N/A |
| Maraviroc 1 | 300 twice daily | 400/100 twice daily | 11 | 1.97 (1.66, 2.34) | 3.95 (3.43, 4.56) | 9.24 (7.98, 10.7) |
| Methadone | 5 single dose | 400/100 capsule twice daily | 11 | 0.55 (0.48, 0.64) | 0.47 (0.42, 0.53) | N/A |
| Nelfinavir | 1000 twice daily combo vs. 1250 twice daily alone | 400/100 capsule twice daily | 13 | 0.93 (0.82, 1.05) | 1.07 (0.95, 1.19) | 1.86 (1.57, 2.22) |
| M8 metabolite | 2.36 (1.91, 2.91) | 3.46 (2.78, 4.31) | 7.49 (5.85, 9.58) | |||
| Nevirapine | 200 once daily twice daily | 400/100 capsule twice daily | 5, 6 3 | 1.05 (0.72, 1.52) | 1.08 (0.72, 1.64) | 1.15 (0.71, 1.86) |
| Norethindrone | 1 once daily (Ortho Novum ®) | 400/100 capsule twice daily | 12 | 0.84 (0.75, 0.94) | 0.83 (0.73, 0.94) | 0.68 (0.54, 0.85) |
| Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir 1 | 25/150/100 + dasabuvir 400 | 400/100 tablet twice daily | 6 | 1.14 (1.01, 1.28) | 1.17 (1.07, 1.28) | 1.24 (1.14, 1.34) |
| 2.04 (1.30, 3.20) | 2.17 (1.63, 2.89) | 2.36 (1.00, 5.55) | ||||
| 1.55 (1.16, 2.09) | 2.05 (1.49, 2.81) | 5.25 (3.33, 8.28) | ||||
| 0.99 (0.75, 1.31) | 0.93 (0.75, 1.15) | 0.68 (0.57, 0.80) | ||||
| Pitavastatin 1 | 4 once daily | 400/100 tablet twice daily | 23 | 0.96 (0.84-1.10) | 0.80 (0.73-0.87) | N/A |
| Pravastatin | 20 once daily | 400/100 capsule twice daily | 12 | 1.26 (0.87, 1.83) | 1.33 (0.91, 1.94) | N/A |
| Rifabutin | 150 once daily combo vs. 300 once daily alone | 400/100 capsule twice daily | 12 | 2.12 (1.89, 2.38) | 3.03 (2.79, 3.30) | 4.90 (3.18, 5.76) |
| 25- O -desacetyl rifabutin | 23.6 (13.7, 25.3) | 47.5 (29.3, 51.8) | 94.9 (74.0, 122) | |||
| Rifabutin + 25- O -desacetyl rifabutin | 3.46 (3.07, 3.91) | 5.73 (5.08, 6.46) | 9.53 (7.56, 12.01) | |||
| Rilpivirine | 150 once daily | 400/100 capsules twice daily | 15 | 1.29 (1.18-1.40) | 1.52 (1.36-1.70) | 1.74 (1.46-2.08) |
| Rosuvastatin 2 | 20 once daily | 400/100 tablet twice daily | 15 | 4.66 (3.4, 6.4) | 2.08 (1.66, 2.6) | 1.04 (0.9, 1.2) |
| Tenofovir alafenamide 1 | 10 once daily | 800/200 tablet once daily | 10 | 2.19 (1.72, 2.79) | 1.47 (1.17, 1.85) | N/A |
| Tenofovir disoproxil fumarate 1 | 300 once daily | 400/100 capsule twice daily | 24 | No Change | 1.32 (1.26, 1.38) | 1.51 (1.32, 1.66) |
| 1 Data extracted from the U.S. prescribing information of co-administered drugs. 2 Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15; 47(5):570-8. 3 Parallel group design N/A = Not available. | ||||||
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