Immunodeficiency Clinic > Drug Information
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Other Names
Kaletra®, ABT-378
HIV aspartic protease is critical in the post-translational processing of the polyprotein products of gag and gag-pol genes into the functional core proteins and viral enzymes. Inhibition of viral protease prevents cleavage of the gag-pol polyprotein thus producing immature, non-infectious virions.
Activity
In vitro activity: in the presence of 50% human serum, mean EC50 of lopinavir against laboratory isolates ranged from 0.04-0.18 ug/mL.
Oral Solution
- 80mg/20 mg per mL oral solution (160 mL bottle); DIN 02243644. (NB: oral solution contains 42.4% alcohol (v/v) and 15.3% (w/v) propylene glycol). Solution should be stored in the fridge until dispensed and then stored up to 42 days at room temperature.
Propylene glycol content: solution (153 mg/mL).
Oral Pellets
- 40mg/10 mg oral pellets packaged in capsules approved by FDA for use in PEPFAR Program (not available in US or Canada).
Tablets
- 200 mg lopinavir/50 mg ritonavir: yellow film-coated tablet, 120 tablets/bottle; DIN 02285533.
- 100/25 mg pale yellow film-coated tablet, 60 tablets/bottle, DIN 02312301.
- Fixed-dose combination tablets of lopinavir/ritonavir/lamivudine or lopinavir/ritonavir/lamivudine/zidovudine are under development.
Capsules
- NB: soft-gel capsules were discontinued in July 2008.
- Combination orange coloured soft-gel capsule (133.3 mg lopinavir/33.3 mg ritonavir); DIN 02243643.
Capsules contain lecithin and coconut oil. In Canada, lopinavir/ritonavir capsules are exposed to soy lecithin. As peanut and soy are from the same plant family, some patients allergic to peanuts may also be allergic to soy (consult an allergist prior to taking capsules).
Propylene glycol content: capsules (64 mg).
Adult and pediatric Kaletra® tablets should be swallowed whole and not chewed, broken, or crushed. Risk of tablets shattering if broken/crushed.
Adults with COVID-19:
Adequate exposures of lopinavir and ritonavir were observed with crushed lopinavir/ritonavir administered via NG tube in 11 adults hospitalized with COVID-19 disease.3581
Children:
Administration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. Therefore, the use of crushed lopinavir/ritonavir tablets should be avoided, if possible.3204
Lopinavir/ritonavir oral solution contains ethanol and is therefore not recommended for use with polyurethan feeding tubes due to potential incompatibility. Feeding tubes that are compatible with ethanol and propylene glycol, such as silicone and polyvinyl chloride (PVC) feeding tubes, may be used.2871
Lopinavir/ritonavir 40mg/10 mg oral pellets packaged in capsules approved by FDA for use in PEPFAR Program (not available in US or Canada). Lopinavir/ritonavir pellets are contained in capsules and should NOT be swallowed whole; should be administered with food. The dose is weight-based and ranges from 2 capsules (80 mg LPV) to 10 capsules (400 mg LPV). The entire content of the capsule should be sprinkled on food and the entire amount consumed, followed by drinking water. Do not crush or chew oral pellets.3360
In the CHAPAS 2 study (infants 3-6 mos) oral lopinavir-ritonavir pellets were added to a small volume of expressed breast milk in a spoon and given to the infant or put directly on the infant’s tongue prior to breastfeeding.3361
- Lopinavir 400 mg/ritonavir 100 mg po BID (2 tablets BID)
- Lopinavir 800 mg/ritonavir 200 mg once daily (4 tablets once daily) in patients with less than 3 mutations associated with lopinavir resistance.
Once-daily dosing is NOT recommended in:
- Patients with ≥3 of the following mutations: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V
- Pediatric patients
- Pregnant patient
With efavirenz or nevirapine:
- Treatment Naïve: LPV 400mg + RTV 100mg po BID (2 tablets BID)
- Treatment Experienced: LPV 600mg + RTV 150mg po BID (3 tablets BID)
Kaletra oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v).
Kaletra oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events.
Neonate (age < 14 days):
- Do not administer to neonates before a postmenstrual age of 42 weeks and a post-natal age of at least 14 days because of potential toxicities.
Infant dose (age 14 days to 12 months)(DHHS Pediatric Guidelines)
- 300 mg/m2 LPV/ 75 mg RTV/m2/dose po BID (~16 mg/kg/dose LPV/ 4 mg/kg/dose RTV po BID)
- Plasma levels among patients < 12 months were lower than those observed in adults or older children. LPV dosing should be adjusted for growth at frequent intervals.
- LPV/RTV is NOT recommended in combination with nevirapine, efavirenz, fosamprenavir, or nelfinavir in patients < 12 months of age.
- Once daily dosing is NOT recommended.
Pediatrics/Adolescent (> 12 months to 18 years) (DHHS Pediatric guidelines):
- Preferred dose for ART-experienced patients with LPV decreased susceptibility
- 300 mg/m2/dose LPV/ 75 mg/m2/dose RTV po BID to a maximum of 400 mg LPV/100 mg RTV BID
- < 15 kg: approximately 13 mg/kg/dose LPV/3.25 mg/kg/dose RTV po BID
- > 15 to 45 kg: approximately 11 mg/kg/dose LPV/2.75 mg/kg RTV po BID
- Dose based on weight for number of 100 mg LPV/ 25 mg RTV tablets:
- 15 to 20 kg: 2 tablets (200/50 mg) po BID
- > 20 kg to 25 kg: 3 tablets (300/75 mg) po BID
- > 25 kg to 30 kg: 3 tablets (300/75 mg) po BID
- > 30 kg to 35 kg: 4 tablets (400/100 mg) po BID (2 tablets that each contain LPV/r 200mg/50mg may be substituted for the 4 LPV/r 100 mg/25 mg tablets in children who are able to swallow larger tablet)
- > 35 kg to 45 kg: 4 tablets (400/100 mg) po BID. (2 tablets that each contain LPV/r 200mg/50mg may be substituted for the 4 LPV/r 100 mg/25 mg tablets in children who are able to swallow larger tablet)
- Once daily dosing is NOT recommended
- Possible dose for ART-naive patients who are > 12 mths; do NOT use if decreased LPV susceptibility
- 230 mg/m2/dose LPV/ 57.5 mg/m2/dose RTV po BID to a maximum of 400 mg LPV/100 mg RTV BID
- < 15 kg: approximately 12 mg/kg/dose LPV/3 mg/kg/dose RTV po BID
- > 15 to 45 kg: approximately 10 mg/kg/dose LPV/2.5 mg/kg RTV po BID
- Dose based on weight for number of 100 mg LPV/ 25 mg RTV tablets:
- 15 to 20 kg: 2 tablets (200/50 mg) po BID
- > 20 kg to 25 kg: 2 tablets (200/50 mg) po BID
- > 25 kg to 30 kg: 3 tablets (300/75 mg) po BID
- > 30 kg to 35 kg: 3 tablets (300/75 mg) po BID
- > 35 kg to 45 kg: 4 tablets (400/100 mg) po BID. (2 tablets that each contain LPV/r 200mg/50mg may be substituted for the 4 LPV/r 100 mg/25 mg tablets in children who are able to swallow larger tablet)
- Once daily dosing is NOT recommended
- Dosing for patients taking nevirapine or efavirenz
- 300 mg/m2/dose LPV/ 75 mg/m2/dose RTV po BID to a maximum of 400 mg LPV/100 mg RTV BID
- < 15 kg: approximately 13 mg/kg/dose LPV/3.25 mg/kg/dose RTV po BID
- > 15 to 45 kg: approximately 11 mg/kg/dose LPV/2.75 mg/kg RTV po BID
- Dose based on weight for number of 100 mg LPV/ 25 mg RTV tablets:
- 15 to 20 kg: 2 tablets (200/50 mg) po BID
- > 20 kg to 25 kg: 3 tablets (300/75 mg) po BID
- > 25 kg to 30 kg: 3 tablets (300/75 mg) po BID
- > 30 kg to 35 kg: 4 tablets (400/100 mg) po BID (2 tablets that each contain LPV/r 200mg/50mg may be substituted for the 4 LPV/r 100 mg/25 mg tablets in children who are able to swallow larger tablet)
- > 35 kg to 45 kg: 4 tablets (400/100 mg) po BID. (2 tablets that each contain LPV/r 200mg/50mg may be substituted for the 4 LPV/r 100 mg/25 mg tablets in children who are able to swallow larger tablet)
- Once daily dosing is NOT recommended
Clinical trial data: LPV/r Pellets
LPV/r 40/10mg pellets are alcohol-free and heat stable; not available in Canada
- Single-arm phase IIIb study3610 evaluated effectiveness, safety, acceptability of LPV/r 40/10mg pellets (BID weight band dosing) in combination with ABC/3TC or AZT/3TC dispersible tablets; enrolled N=990 children living with HIV weighing 3 to <25kg who were ARV naive, on liquid LPV/r-based or failing NNRTI-based ART. Median age 36 months (IQR 20-56), median weight 12 kg (IQR 9 to 15), median baseline VL (log10 copies/mL) 2.8 (IQR 1.6-4.7), median CD4 1459 (IQR 986-1995)
- Primary effectiveness composite (alive and on study drug with HIV VL<1000 copies/mL) at 48 weeks: 683/990 (69%); VL>1000 copies/mL: 169/990 (17%); premature discontinuation: 97/990 (10%).
- Treatment related adverse events: 75/990 (8%); most frequent was diarrhea (3%). Serious adverse events: 157 events in 88 children, 1 event of grade 3 diarrhea assessed as treatment related.
- Acceptability: 80% and 93% caregivers described as easy or very easy to administer; 88% and 94% caregivers reported children accepted pellets well.
- Conclusion: LPV/r pellets plus ABC/3TC or AZT/3TC were well-tolerated, effective and well-accepted in a large cohort of children, including children <24 months with advance disease
Administer doses with a calibrated oral dosing syringe.
- Solution: Take with food to enhance absorption.
- Tablets: Take with or without food.
100 mg lopinavir/25 mg ritonavir pediatric tablet;
200 mg lopinavir/50 mg ritonavir adult tablet, may be used in children capable of swallowing larger tablets.
Kaletra oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. Kaletra oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity, lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving Kaletra oral solution.
Tablets should be swallowed whole and not chewed, broken, or crushed. Risk of tablets shattering if broken/crushed. Administration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. Therefore, the use of crushed lopinavir/ritonavir tablets should be avoided, if possible.[Best et al. JAIDS 2011;58:385-91]
In a prospective study of HIV-infected patients on hemodialysis taking lopinavir/ritonavir capsules 400/100 mg BID (n=13), 12-hour PK was assessed. Mean Cmin, Cmax, and AUC were 2.76 mg/mL, 8.45 mg/mL and 69.6mg h/mL for lopinavir and 0.08mg/mL, 0.58mg/mL and 3.74mg h/mL for ritonavir. The AUC geometric mean ratios (90% CI) for LPV and RTV were 81% (67, 97), and 92% (76, 111), respectively. LPV Cmin was lower than expected in the hemodialysis group.
No dosing adjustments are required in treatment-naïve patients. May wish to consider TDM in treatment-experienced patients. May administer drug regardless of hemodialysis schedule. [Gupta et al. 2008]
CrCl (mL/min) for men: 〈(140 - age) (weight kg) x 60〉 / 〈(serum creatinine umol/L) (50)〉 CrCl (mL/min) for women: as above multiplied by 0.85 |
No dosage recommendation available, use with caution in hepatic impairment.
Steady-state 12-hour lopinavir/ritonavir pharmacokinetic profiles were assessed in 15 HIV-positive patients coinfected with HCV/HBV (Child-Pugh class A) taking 400/100 mg BID; data were compared to an HIV-positive cohort without hepatitis. Lopinavir pharmacokinetics were not altered in the presence of chronic HBV/HCV coinfection compared to the cohort without hepatitis.[von Hentig et al. 2010].
Steady-state 12-hour lopinavir/ritonavir pharmacokinetic profiles were assessed in 12 HIV/HCV coinfected patients with mild (Child-Pugh score = 5) and moderate (Child-Pugh score = 7-9) hepatic impairment, and in 12 HIV-infected patients without liver impairments matched for sex and weight (control). Hepatic impairment resulted in a 30% increase in total lopinavir AUC, a 20% increase in Cmax, and a 79% increase in Cmin, compared to the control group. Severity of liver dysfunction (mild vs moderate) did not affect lopinavir pharmacokinetic profiles. The percentage of lopinavir unbound in the hepatic impairment groups was higher than that in the control group. [Peng et al. 2006]
Capsules/solution:
Administration with a moderate fat meal (500-682 kcal, 23-25% calories from fat) increases lopinavir AUC 48%, Cmax 23%. Administration with a high fat meal (872 kcal, 56% calories from fat) increases lopinavir AUC 97%, Cmax 43%. Take capsules or oral solution with food.
Tablets:
Tablets may be taken with or without food.
No clinically significant changes in Cmax and AUC were observed following administration of Kaletra tablets under fed conditions compared to fasted conditions. Relative to fasting, administration of KALETRA tablets with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 26.9% and 17.6%, respectively. Relative to fasting, administration of KALETRA tablets with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC by 18.9%, but not Cmax.
1) A case of a 38‐year‐old woman with HIV infection and non‐Hodgkin's lymphoma affecting the stomach who underwent total gastrectomy and esophagojejunostomy followed by Roux‐en‐Y reconstruction was noted to have a lopinavir serum trough concentration at steady state of 4864 ng/mL on a dose of 400 mg twice daily, comparable to reference ranges. 3397
2) A case of a 28‐year‐old man with a history of AIDS‐related duodenal lymphoma who underwent gastrojejunal bypass demonstrated adequate lopinavir serum levels when administered through the bypass with a fatty meal. The steady‐state trough concentration of lopinavir when administered in this fashion was 20 830 ng/mL, which is in contrast to a concentration of <200 ng/mL when lopinavir was administered with a fatty meal by jejunal tube. 3398
Lopinavir is a substrate and weak inhibitor of CYP3A4.
Potential for interactions with other enzyme inducers or inhibitors [see also Interactions with Ritonavir].
Oral Bioavailability:
Not established in humans.
Protein Binding:
98-99% (alpha-1-acid glycoprotein and albumin)
Tmax:
4 hours
Serum T½:
5-6 hours
Metabolism:
- CYP3A4 substrate
- Inhibits CYP3A4, 2D6 (to lesser extent)
- Induces glucuronyl transferases and possibly CYP1A2, CYP2C19 and 2C9
Excretion:
After multiple dosing, < 3% lopinavir excreted unchanged in urine
Ctrough 7.1 ± 2.9 ug/mL, Cmin 5.5 ± 2.7 ug/mL, AUC 92.6 ± 36.7 ug.h/mL
Body weight is a significant predictor of lopinavir kinetics (AUC, Cmax); subjects with lower body weight tend to have higher lopinavir Cmax and AUC [Bertz 2001]
In vivo intracellular accumulation: cell/plasma ratio 0.65-1.55 when dosed with ritonavir.
23 Thai HIV infected children (age 2-18 years) were randomized to standard dose of LPV (according to WHO dosing table) or low dose of LPV (70% of recommended dose); NRTI backbone was AZT + 3TC, kinetic study done at 4-6 weeks.
LPV/r standard dose N = 11 | LPV/r low dose N =12 | |
Median dose | 288 mg/m2 BID | 194 mg/m2 BID |
Mean AUC 0-12hr | 107.1 h.mg/L | 84.6 h.mg/L |
Mean Cmax | 11.9 mg/L | 9.8 mg/L |
Mean Cmin | 5.2 mg/L | 3.8 mg/L |
1 child in low dose group had subtherapeutic LPV/r concentration (< 1mg/L). There was no statistical difference in CD4 and VL between the groups (van Der Lugt et al. 2008).
Comparison of lopinavir and ritonavir tablet and soft gelatin capsule (SGC) pharmacokinetics in antiretroviral naive HIV-1 infected subjects:
- LPV/r 400mg/100mg BID: Tab formulation: LPV conc ↑ 14-25% VS SGC;
- LPV/r 800mg/200mg OD: Tab formulation: LPV conc ↑19-38% VS SGC [Klein et al. 2008]
Fixed-dose combination tablets of lopinavir/ritonavir/lamivudine or lopinavir/ritonavir/lamivudine/zidovudine shown to be bioequivalent to the individual marketed products under fasting conditions. The food effect on both fixed-dose combinations is similar to that of the marketed products. [Salem et al. 2014 IWCPHT]
10 HIV infected adults taking LPV/RTV 400/100mg BID for > 4 weeks. Subjects were given their morning dose with a standardized breakfast. 8 plasma samples were drawn over a 12 hr period, 1 CSF sample was drawn
- Median LPV Plasma kinetics: AUC: 71.3 h.ug/ml, Cmin 3.82ug/ml, Cmax 9.38 ug/ml, Conc at 9hrs: 5.42 ug/ml
- Median CSF kinetics (IQR): Conc at 9hrs: 11.2 ng/ml (6.76-16.4),
- CSF: Plasma Ratio: 0.225% (0.194-0.324)
Authors state end of dosing interval LPV CSF concentrations were above the median IC50 for wtHIV-1 for this dosing regimen [Dicenzo et al. 2009].
2010 CNS Penetration Effectiveness (CPE) Score: 3 [Letendre S et al. 2010]
Note: For more complete information and the most current safety data on antiretrovirals in pregnancy refer to the current US DHHS Perinatal Guidelines.
Pregnancy risk category C. Limited experience in human pregnancy. When dosed at normal adult doses in pregnancy, lower than optimal drug concentrations may be seen.
In a prospective, nonblinded, pharmacokinetic study in HIV-infected pregnant women, 33 subjects received 2 lopinavir tablets (400/100 mg) BID during the 2nd trimester, 3 tablets (600/150 mg) BID in the 3rd trimester, and 2 tablets (400/100 mg) BID post-delivery through 2 weeks postpartum. Median lopinavir AUC was 72, 96 and 133 ug.hr/mL and median lopinavir Cmin was 3.4, 4.9 and 6.9 ug/mL in the 2nd trimester, 3rd trimester and postpartum, respectively. Recommend using higher lopinavir dose in 2nd and 3rd trimesters of pregnancy to achieve exposures similar to those in non-pregnant subjects taking standard LPVr. May reduce to standard lopinavir dosing postpartum.[Best et al. 2010].
In a prospective longitudinal PK study of 12 HIV-infected women on lopinavir/r 400/100 mg BID who underwent intensive PK evaluations of total (protein-bound and unbound) and unbound lopinavir/r during and after pregnancy, total LPV AUC was significantly lower than postpartum AUC (p=0.005), but unbound LPV AUC and C12h remained unchanged during pregnancy despite a 25% dose increase in the last trimester. These findings suggest that dose adjustments may not be required in all HIV-infected pregnant women.[Patterson et al. 2013]
In 23 HIV-infected pregnant women receiving lopinavir/ritonavir (all VL< 40 copies/mL at delivery), mean lopinavir cord blood concentration was 369.3 ng/mL (78.2% were below cut-off values). Mean amniotic fluid:maternal plasma ratio for lopinavir was 0.06. Undetectable viral load was found in amniotic fluid and cord blood.[Ivanovic et al. 2010].
Lactation
Secreted into breast milk of lactating rats.
Call 1-800-258-4263 to register patients in Antiretroviral Pregnancy Registry.
Mutations in the protease gene associated with resistance to lopinavir (IAS-USA Fall 2017 Resistance Mutations):
- Major: V32I, I47V/A, L76V, V82A/F/T/S
- Minor: L10F/I/R/V, K20M/R, L24I, L33F, M46I/L, I50V, F53L, I54V/L/A/M/T/S, L63P, A71V/T, G73S, I84V, L90M
In PI-experienced patients, accumulation of 6 or more mutations is associated with reduced virologic response.
There are emerging data that specific mutations, most notably I47A (and possibly I47V) and V32I are associated with high-level resistance. The addition of L76V to 3 PI resistance-associated mutations substantially increases resistance to lopinavir.
Phenotypic data on clinical virus isolates associated with various mutations using ViroLogic PhenoSenseTM (http://hivdb.stanford.edu/):
- 54V, 82A, 90M: 20-fold ↑
- 46L, 54V, 82A, 90M: 33-fold ↑
- 46I, 54V, 82A, 90M : 142-fold ↑
- 46L, 48V, 54V, 82A, 90M: 55-fold ↑
- 46I, 54V, 82T, 84V, 90M: 75-fold ↑
- 46L, 48V, 54T, 82A : 75-fold ↑
Varying degrees of cross-resistance with other PIs showed greater ↓ susceptibility to lopinavir
GI: abnormal stools, diarrhea, nausea, vomiting (higher incidence with QD dosing), abdominal pain, asthenia.
Other: Protease class effects include: hyperlipidemia, hypertriglyceridemia, hyperglycemia, fat maldistribution, weight gain, increase in LFTs, hepatitis, increased bleeding in hemophiliacs, osteonecrosis.
Baseline Assessment
Assess risk factors for diabetes, coronary artery disease, osteonecrosis (i.e. steroids, ETOH, diabetes, hyperlipidemia), and hepatic dysfunction (i.e. HBV/HCV, ETOH use). CBC/diff, LFTs, glucose, fasting cholesterol profile.
Routine Labs
CBC/diff, LFTs, glucose every 3 mos.
Fasting lipids (8-12 hr level) every 3-6 months post-therapy, then annually. If TG > 2.3 mmol/L at baseline, repeat after 1-2 months.
Solution: Stable in refrigerator until expiry date. Stable at room temperature (< 25°C) for 2 months.
Tablets: Store film-coated tablets at 20°- 25°C; excursions permitted to 15°-30°C. Exposure of tablets to high humidity outside the original container for longer than 2 weeks is not recommended.
Abbvie