Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition

Abstract

Toxoplasmic encephalitis is one of the leading causes of morbidity in patients with AIDS. Lifelong treatment is needed to prevent relapses, and primary prevention is desirable in high-risk patients, but the available drugs are often poorly tolerated. Azithromycin (AZM) has been considered a drug candidate because of its efficacy in the animal model and its kinetic properties, which would allow intermittent administration. The tolerability and kinetics of AZM and its effect on the disposition of zidovudine (ZVD) were therefore evaluated in a preliminary open study in nine human immunodeficiency virus-infected patients. AZM was administered once weekly for 5 weeks 2 h before the usual morning ZVD dose. The day before and on the first and fifth AZM dosings, blood samples were drawn every 30 min during 5 h for determination of the concentrations of ZVD and its glucuronide metabolite. Blood samples were drawn for AZM measurement over 72 and 360 h on the first and fifth AZM administrations, respectively, as well as before and 3 h after dosing on the second, third, and fourth AZM dosings. After the first and fifth administrations, maximum AZM concentrations in serum were 0.6 + 0.1 and 0.8 ± 0.2 ,uM (mean + standard error of the mean), respectively; times to peak concentration in serum were 3.7 ± 0.2 and 2.9 + 0.4 h, respectively; areas under the plasma concentration-time curves were 9.2 ± 1.6 and 9.3 + 2.0 ,ug h/ml, respectively; and half-lives were 61.0 + 5.4 and 63.8 ± 6.7 h, respectively.On days -1, 1, and 29, ZVD kinetic parameters were as follows: maximum concentrations in serum, 3.1 + 0.6, 4.3 + 0.6, and 4.2 + 0.9 ,uM, respectively; times to maximum concentration in serum, 1.1 + 0.4, 0.8 ± 0.2, and 1.2 ± 0.3 h, respectively; areas under the plasma concentration-time curves, 5.3 + 0.9, 5.9 + 0.6, and 5.7 + 0.8 ,ig. h/ml, respectively; and half-lives, 1.3 + 0.08, 1.4 ± 0.04, and 1.3 + 0.04 h, respectively. Except for transient mild abdominal cramps that occurred at 2 to 3 h postdose (6 of 45 exposures) and nausea (4 of 45 exposures), neither subjective nor objective side effects were observed. The kinetics of AZM were similar after the first and repeated administrations, and the disposition of ZVD was not altered by this treatment. The efficacy of AZM in preventing cerebral toxoplasmosis can therefore be safely tested in human immunodeficiency virus-infected patients concomitantly treated with zidovudine.

The Effect of Azithromycin on the Pharmacokinetics of Indinavir

“…Our findings show that a single 1200 mg dose of azithromycin does not significantly alter the pharmacokinetics of indinavir in healthy volunteers. This finding is concordant with the low in vitro binding of azithromycin to CYP 3A4 15 and the previously reported lack of interaction in studies with other agents used for the treatment of HIV, such as zidovudine 16,17 and didanosine. 18 There is a possibility that a significant change in some pharmacokinetic parameters of indinavir may be observed with repeated chronic concomitant administration of azithromycin, but the effect is unlikely to have clinical relevance.…”

Azithromycin for the treatment of acne

“…No pharmacokinetic drug–drug interactions have been observed in trials studying the concomitant use of azithromycin and other medications, including terfenadine and theophylline. 9–12 The unique pharmacokinetics of azithromycin make it a highly suitable agent for the treatment of acne. Significant intracellular concentrations of azithromycin find their way to body sites where inflammatory cells are present, allowing the delivery of the effective agent at the focal point at which it is needed.…”

Evaluation of the efficacy of prolonged administration of azithromycin in a murine model of chronic toxoplasmosis

“…Azithromycin was selected because of the following properties: prolonged inhibition of the replication of intracellular tachyzoites (Chamberland, Kirst & Current, 1991); in-vitro activity against cyst forms (Huskinson-Mark, ; high tissue specificity, with concentrations in the brain which are almost ten-fold higher than those in serum after oral dosing (Araujo, Shepard & Remington, 1991); significant intracellular accumulation (Gladue el ai, 1989); and potent activity in experimental murine toxoplasmosis (Araujo, Guptill & Remington, 1988;Araujo et al, 1991;Derouin et al, 1992). A number of additional observations also suggested that azithromycin might be suitable in this context: a prolonged half-life (Girard et al, 1987), thereby allowing a simplified dosing schedule; good tolerability; lack of effect on zidovudine disposition in patients with AIDS (Chave et al, 1992); and potential activities against cryptosporidium and the Mycobacterium avium complex (Brown et al, 1993;Vargas et al, 1993). The 100-mg/kg/day dosage was used because it corresponds to that which is appropriate for man after size correction.…”