Conflicting pharmacokinetic results when lopinavir and atazanavir are double-boosted with ritonavir

The double boosted combination of twice-daily lopinavir/ritonavir (Kaletra) with once-daily atazanavir (Reyataz) may significantly increase or reduce C_min (minimum) plasma lopinavir levels, according to conflicting results from two small studies examining pharmacokinetic interactions between the three protease inhibitors (PIs), recently published in the journals AIDS and Antiviral Therapy. However, both studies agree that the combination does not appear to adversely affect levels of atazanavir or ritonavir, and that the combination is generally well tolerated.

The use of double-boosted PIs - where low-dose ritonavir is utilised to increase exposure to two active PIs - is currently an experimental option for highly treatment-experienced individuals with multidrug resistant HIV. Double-boosting PIs is also an experimental nucleoside-sparing option for antiretroviral-naive individuals.

Atazanavir appears to be a good candidate for dual boosting since it has a different resistance and side-effect profile to lopinavir and it can be taken once-daily. However, little is known regarding pharmacokinetic interactions between the three PIs and how boosting with 200mg daily ritonavir, rather than the approved 100mg daily dose, might affect tolerability and efficacy.

Surprisingly, until this year no studies had been published reporting pharmacokinetic interactions between Kaletra and atazanavir, although portions of the study by Ribera and colleagues had previously been presented at the 2005 European Drug Resistance Workshop in Athens, and a study by Langman and others (showing no significant PK effects) was presented at the 2005 Workshop on Clinical Pharmacology of HIV Therapy in Quebec.

Significantly increased lopinavir and atazanavir levels

Ribera and colleagues from Hospital Universitari Vall d'Hebron in Barcelona, Spain, enrolled 16 individuals with a median of four prior highly active antiretroviral regimens (and six previous regimens that may have included mono- or dual therapy) in a non-randomised, open-label pilot study.

Two participants switched to lopinavir/ritonavir 400mg/100mg twice daily and atazanavir 300mg once daily due to intolerance to their previous drugs, and already had viral loads loads below 50 copies/ml. The remaining fourteen began this combination after virological failure with their previous regimen and at baseline all fourteen had extensive nucleoside resistance. In addition, thirteen had between one and eight genotypic protease mutations.

After at least a month of Kaletra/atazanavir therapy - taken with a background regimen that included tenofovir, or ddI (Videx EC), or T20 (Fuzeon), or combinations that included d4T and abacavir, T20 and ddI, and T20, tenofovir and 3TC - and intensive TDM was performed up to twelve hours post-dosing.

Results were compared with historical data from two recently published studies, comprising 15 individuals taking lopinavir/ritonavir 400mg/100mg twice daily and 25 individuals taking lopinavir/ritonavir 400mg/100mg twice daily with saquinavir 1000mg once daily. In addition, the investigators included a third comparison group of 15 consecutive patients from the same Barcelona clinic who were receiving atazanavir/ritonavir 300mg/100mg once daily.

Compared to historical controls taking Kaletra alone or Kaletra with saquinavir, concentrations of lopinavir were found to be significantly higher in the Kaletra/atazanavir group. Median twelve hour area AUC values were 115.7µg/h/ml in those taking Kaletra/atazanavir, compared with 85.2 µg/h/ml in those taking Kaletra alone (p=0.019) and 85.1 µg/h/ml in those taking Kaletra with saquinavir (p=0.006).

Similarly, higher Cmax and Cmin values were also seen in the Kaletra/atazanavir arm. C_max values were 12.2 µg/ml, compared with 9.5 µg/ml ml in those taking Kaletra alone (p=0.043) and 10.0 µg/ml in those taking Kaletra with saquinavir (p=0.037). Cmin values were 9.1µg/ml, 5.6µg/ml (p=0.013) and 5.5µg/ml (p=0.001), respectively.

Compared to the individuals taking atazanavir with just 100mg ritonavir daily, no difference was seen for atazanavir AUC or C_max concentrations. However, atazanavir Cmin values were significantly higher in those taking atazanavir with lopinavir/ritonavir 1.07 (0.61-1.79) µg/ml versus 0.58µg/ml (p = 0.001). The investigators suggest that this difference was likely due to the additional 100mg ritonavir daily dose in those taking Kaletra.

No differences were seen in the concentrations of ritonavir between the three arms where the same 100mg twice-daily dose was administered.

Significantly reduced minimum lopinavir levels

Colombo and colleagues from the University Hospital of Lausanne, Switzerland, enrolled into a pharmacokinetic study thirteen treatment-experienced individuals currently on a virologically successful antiretroviral combination that included either three softgel capsules of Kaletra twice daily (n=7) or 300mg atazanavir/100mg ritonavir once daily (n=6). The background regimens contained a combination of two nucleosides, including d4T (Zerit), AZT (Zidovudine), tenofovir (Viread), abacavir (Ziagen), and 3TC (Epivir).

Intensive therapeutic drug monitoring (TDM) performed over a 24-hour period on day 1 obtained total plasma drug concentrations. On day 2, 300mg atazanavir was added to the Kaletra arm and Kaletra replaced the 100mg ritonavir boosting dose in the atazanavir arm. Similarly intensive TDM was performed on day 14.

A reduction in the mean total plasma concentration of lopinavir was seen on day 14 after the addition of atazanavir. Significantly, the C_min fell by a third, from 4,049 ng/ml to 2,840 ng/ml (pmax (maximum) values.

However, no significant differences were seen in atazanavir levels, even though twice the dose of ritonavir was used. Levels of ritonavir were not affected in either arm.

Why the differences?

The Lausanne study used the same patients for comparison before and after each drug was added into a successful (and successfully tolerated) existing regimen. This ought to have yielded a more reliable comparison than the Barcelona study, which used historical controls for lopinavir levels. However, the numbers in both studies were very small, and both investigators note extremely wide "within-day and between-day" drug levels, as well as "wide inter-patient variability".

It should also be noted that Langham and colleagues found no significant differences in the levels of either atazanavir or lopinavir when they studied the drugs in combination in 28 highly treatment-experienced patients.

Colombo and colleagues argue that although they saw lower levels of lopinavir in their study, "the clinical significance of this limited...decrease...is unknown, as it is within the range of inter-individual PK variability that characterises exposure to this drug."

In 'real-life' terms, however, Ribera and colleagues found that, at least in the short term (24 weeks), the combination of Kaletra with atazanavir "had substantial antiviral efficacy" in their patients with remarkably extensive antiretroviral experience and resistance profiles.

Nevertheless, it may well be prudent to consider individualised dosage adjustment of Kaletra based on steady-state TDM when using this combination, particularly in extensively-treated individuals with major protease mutations.

Small adjustments may be difficult, however, since the soft-gel formulation of Kaletra that was used in both studies has already been replaced in North America with a new tablet formulation, and this should also occur in Europe within the next few months. It is also possible that the interactions seen with the soft-gel formulation may differ with the tablet formulation.

Nevertheless, Ribera and colleagues conclude on a cautiously optimistic note, calling for "further studies...to confirm these encouragingly preliminary results."

Tolerability and efficacy

Despite the higher concentrations of both lopinavir and atazanavir seen in the Kaletra/atazanavir arm of the Barcelona study, the treatment was generally well-tolerated and was not discontinued because of adverse effects. Expected side-effects associated with lopinavir (self-limiting diarrhoea in six participants) and atazanavir (mild hyperbilirubinaemia in all sixteen, including four cases of yellowing of the whites of the eyes or jaundice) were seen, however.

Notably, thirteen of the sixteen achieved viral loads below 50 copies/ml by week 24, a "substantial efficacy" which the investigators partially attribute to the high levels of lopinavir and atazanavir achieved. The do note, however, that there may have been a selection bias in their small cohort which may have led to better Kaletra tolerance given the high levels of lopinavir seen: "a large number of patients included had already received or were receiving [Kaletra] with good tolerance, whereas patients who had previously shown poor tolerance to these drugs were not considered for this treatment."

Not surprisingly, since the Lausanne patients were only on the Kaletra/atazanavir combination for fourteen days, and lower lopinavir levels were observed, the combination was also well-tolerated. Of note, three individuals experienced diarrhoea when Kaletra was added to their atazanavir-containing regimen, and four individuals experienced mild hyperbilirubinaemia when atazanavir was added to their Kaletra-containing regimen. These adverse effects reversed two weeks after removing the respective drugs. No virological failures were seen.