Lopinavir

Pharmacokinetics

From 122 outpatients, 748 lopinavir and 748 ritonavir plasma concentrations were available for analysis [ ]. The interaction between the drugs was described by a time-independent inverse relation between exposure to ritonavir over a dosing interval and the apparent oral clearance (CL/F) of lopinavir. No patient characteristics, other than the use of NNRTIs had a significant effect on the pharmacokinetics of lopinavir combined with ritonavir.

From 186 patients in an Amsterdam clinic, 505 ritonavir plasma concentrations at a single time and 55 full pharmacokinetic profiles were available, resulting in a database of 1228 plasma ritonavir concentrations [ ]. The concomitant use of lopinavir resulted in a significant 2.7-fold increase in the clearance of ritonavir. No patient characteristics affected the pharmacokinetics of ritonavir.

General adverse effects and adverse reactions

In early monotherapy studies, including 62 and 87 patients [ , ], in whom the potent antiretroviral effect of ritonavir was first demonstrated, the most common adverse events were nausea, diarrhea, headache, circumoral paresthesia, and altered taste sensation. Nausea, vomiting, and diarrhea are common during the start of therapy and usually disappear over the first few weeks of treatment. These adverse reactions can be markedly reduced by using a step-up approach, increasing to the full dose over 6 days. General weakness, circumoral paresthesia, and taste disturbance occur in 5–10% of patients and are seldom dose-limiting.

Ritonavir does not have a broad therapeutic margin, and patients with higher ritonavir concentrations are at a higher risk of neurological or gastrointestinal adverse effects. It is feasible to individualize the dosage regimen with the aid of plasma concentration measurement and close observation of adverse reactions, and there is a close relation between the two; this may enable one to increase substantially the percentage of patients who tolerate ritonavir without risking underdosage [ ].

An important consideration in the use of all HIV-1 protease inhibitors, but of ritonavir in particular, is their potential for drug interactions through their effects on cytochrome P450 isoenzymes. Interactions of ritonavir with other anti-HIV drugs have been reviewed [ ].

Observational studies

In studies of combining ritonavir with fluconazole [ ] and ritonavir with mefloquine [ ] there were no significant adverse reactions, and dosage adjustment is not warranted.

Placebo-controlled studies

In a randomized, double-blind study in 70 patients taking a regimen containing protease inhibitors, lopinavir + ritonavir 400/100 mg or 400/200 mg bd was substituted [ ]. On day 15 nevirapine 200 mg bd was added and NRTIs were changed to include at least one NRTI not previously taken. Despite a more than four-fold reduction in phenotypic susceptibility to the pre-entry protease inhibitor in 63% of the patients, mean plasma HIV-1 RNA concentrations fell by 1.14 log copies/ml after 2 weeks. At week 48, 86% had plasma HIV-1 RNA concentrations of under 400 copies/ml, and 76% under 50 HIV-1 RNA copies/ml. Mean CD4 cell counts increased by 125 cells/μl. The most common adverse events were diarrhea (n = 16) and weakness (n = 4). There were rises in gamma-glutamyltransferase activity (n = 18), total cholesterol (n = 17), and triglycerides (n = 17), and transient rises in aminotransferase activities (n = 11). Three patients discontinued therapy because of drug-related adverse events.

Cardiovascular

Two of 16 patients taking lopinavir + ritonavir developed so-called inflammatory edema, which resolved on withdrawal and recurred after rechallenge [ ]. In three of eight patients inflammatory edema occurred 1–4 weeks after they started to take regimens that contained lopinavir + ritonavir [ ]. The edema affected the feet, ankles, and calves and was associated in one case with fever and in another with a transient rash; in one case the left shoulder and groin were also affected. All three recovered completely within 1–4 weeks despite continued drug treatment, but 7 months later one had a relapse that required withdrawal of lopinavir + ritonavir.

From a case in which there was positive dechallenge and rechallenge it has been concluded that edema of the lower limbs can be an adverse effect of ritonavir in some HIV-positive patients [ ]. The authors suspected a relation to the drug’s vasodilatory activity. However, it should also be borne in mind that ritonavir has caused reversible renal insufficiency, which should be looked for in any patient who develops edematous changes.

Nervous system

Myasthenia has been attributed to ritonavir [ ].

• A 71-year-old man with an 8l-year history of HIV infection developed slurred speech, difficulty in climbing stairs, bilateral ptosis, and lateral rectus weakness 3 weeks after having started to take ritonavir (1200 mg/day). All his signs worsened with prolonged testing, and edrophonium produced improvement in ptosis and speech. Specific electromyographic testing confirmed myasthenia gravis. Computed tomography of the chest was normal. After withdrawal of ritonavir the signs and symptoms partly resolved by 3 months.

A definite causal link with ritonavir could not be established, but the authors speculated that ritonavir may have unmasked myasthenia gravis in this patient.

Sensory systems

Ototoxicity has been attributed to lopinavir + ritonavir [ ].

• A 46-year-old man took a regimen containing lopinavir + ritonavir, and 4 weeks later complained of reduced auditory acuity accompanied by lancinating pain. Audiology showed mild to moderate bilateral sensorineural hearing loss. On withdrawal and use of efavirenz his hearing recovered.

Based on the time-course and the effect of withdrawal, lopinavir/ritonavir appears to have been the causative agent in this case.

Endocrine

In five of 19 adolescents with HIV infection who took inhaled or intranasal fluticasone and low-dose ritonavir there was associated laboratory evidence of adrenal suppression [ ]. There were clinical features of Cushing syndrome, especially weight gain, in most of these patients, with laboratory evidence of adrenal suppression from exogenous corticosteroids. Both the laboratory abnormalities and the Cushingoid feature resolved when the fluticasone and/or ritonavir were withdrawn in four of the five cases.

Six patients with pre-existing HIV-associated lipodystrophy developed symptomatic Cushing’s syndrome when treated with inhaled fluticasone at varying doses for asthma while concurrently taking low-dose ritonavir-boosted protease inhibitor antiretroviral regimens for HIV infection [ ]. Stimulation studies showed evidence of adrenal suppression in all patients. After withdrawal of inhaled fluticasone, four patients developed symptomatic hypoadrenalism, and three required oral glucocorticoid support for several months. Other complications included evidence of osteoporosis (n = 3), crush fractures (n = 1), and exacerbation of pre-existing type 2 diabetes mellitus (n = 1).

Metabolism

In 19 patients taking lopinavir + ropinavir, either 533/133 mg bd (in patients co-treated with NNRTIs) or 400/100 mg bd, there were increases in triglyceride and total cholesterol concentrations after 4 weeks; seven patients developed grade 2 or worse rises in lipids and three patients developing grade 3 hyperlipidemia. HDL cholesterol increased over the course of 48 weeks, but LDL did not change significantly [ ]. At baseline nine patients had lipodystrophy but that did not worsen over the next 48 weeks. However, CT-based standardized analysis showed an increase in total abdominal fat (+ 14%) and a loss of limb fat (− 8%) in the 16 patients who completed the study. There was a significant correlation between lopinavir trough concentrations and changes in limb fat, but no association between lopinavir concentration and changes in total abdominal fat, visceral fat, or subcutaneous abdominal fat. The authors cautioned against interpreting these data as showing a causative relation between lopinavir and lipodystrophy, as the study population was rather small and confounding elements could not be ruled out. However, they advised the use of plasma concentration measurement in order to avoid unnecessarily high lopinavir concentrations, which may be associated with lipodystrophy.

In contrast, in 55 patients taking lopinavir + ropinavir, even though there was a significant increase in triglyceride concentrations over 12 weeks, this did not correlate with higher plasma lopinavir concentrations [ ]. The authors cautioned against premature dosage adjustments pending larger studies to elucidate this phenomenon.

Gastrointestinal

The most common adverse reaction associated with ritonavir boosted lopinavir is diarrhea [ ].

In a prospective, randomized trial in 100 patients, the most common adverse reactions to lopinavir + ritonavir included abnormal stools, diarrhea, and nausea [ ].