The International Workshop on the Clinical Pharmacology of HIV Therapy was founded six years ago as a forum for the exchange of primary data to better understand the disposition and rational use of antiretroviral drugs. Since then, the meeting has grown from a small rehash of CROI to a major international meeting in its own right, attracting over 200 participants and more than 100 presented abstracts. This is now pharmacology’s equivalent of the annual Resistance Workshop, which interestingly is organized by the same company. The 6th International Workshop on the Clinical Pharmacology of HIV Therapy was held in Quebec City in April at the historic Chateau Le Frontenac Hotel, and included the first public presentation of several important drug interaction and toxicity studies. A complete summary of the meeting is available at http://www.hivpresentation.com.

H₂-Blockers and Atazanavir

Recent data on the profound reduction in atazanavir (ATV) concentrations with coadministration of the proton pump inhibitor (PPI) omeprazole [HHR 2005; 17(3):6] have raised concerns that this promising PI might not be useful in patients taking other medications to counteract gastric acidity. The bioavail-ability of atazanavir is highly dependent on low gastric pH, and the assumption after the 12th CROI was that H₂-blockers and antacids were likely to have the same effect on atazanavir as PPIs.

Sangeeta Agarwala and colleagues from Bristol Myers-Squibb presented results of a healthy volunteer pharmacokinetic interaction study between atazanavir and the H2-antagonist famotidine [Abstract 11)]. As a reference regimen, healthy volunteers received ATV 300 mg with ritonavir 100 mg QD for 10 days. Taking this regimen with concurrent famotidine (40 mg BID) reduced the geometric mean AUC by 18% and the trough (C_min) by 28% (see Table 1). However, increasing the ATV dose from 300 to 400 mg in the presence of famotidine resulted in an AUC and C_min that were no different from that of the reference regimen.

A separate group of healthy volunteers received the reference regimen of ATV 400 mg QD for 6 days. Compared to this reference regimen, taking ATV 400 mg with famotidine reduced the geometric mean AUC by 41% and the C_min by 42% (see Table, p 1). However, if ATV was taken 10 hours after the previous famotidine dose and two hours before the next dose, the AUC and Cmin were unchanged. Drinking 8 ounces of an acidic beverage (cola) did not reverse the effects of famotidine on ATV, although the cola and the ATV were given with a light meal, which probably offset the acidity of the beverage.

The results of this study suggest that H₂- antagonists such as famotidine can be used safely in patients taking ATV who require treatment for gastric hyperacidity. For patients taking boosted ATV/r, the ATV dose should be increased to 400 mg QD with 100 mg of ritonavir. For patients taking unboosted ATV, the drug would have to be taken at least two hours before the morning famotidine dose; it should be pointed out that this greatly complicates administration of ATV and reduces the convenience of this PI. Some would argue that the preferred regimen for patients who need ATV and an H₂-antagonist would be the RTV-boosted regimen of 400/100 mg QD, which can be taken at the same time as the H₂-blocker.

In related presentations, researchers from Tibotec reported that the bioavailability of the investigational protease inhibitor TMC- 114 was not affected by coadministration of omeprazole 20 mg QD or ranitidine 150 mg BID [Sekar V, et al. Abstract 17], and investigators from GlaxoSmithKline found no effect of esomeprazole on the bioavailability of fosamprenavir [Shelton, M, et al. Abstract 24)].

Ritonavir and Corticosteroids

Ritonavir (RTV) is a potent inhibitor of the drug metabolizing enzyme cytochrome P450 (CYP) 3A4, and new clinically important interactions with this agent continue to be reported. For example, in early 2005, the FDA required a black box warning and “Dear Doctor” letter about the effect of RTV on the intranasal corticosteroid fluticasone. Concurrent RTV increased the fluticasone systemic AUC by 350-fold, which was associated with a mean 86% drop in plasma cortisol concentrations and Cushingoid features in some patients.

Signs of Cushing’s syndrome, as well as osteonecrosis, have also been reported anecdotally in patients taking oral corticosteroids and RTV, but the magnitude of the pharmacokinetic impact of RTV on drugs like prednisone has not been evaluated directly. Scott Penzak and colleagues from the NIH Clinical center in Bethesda reported results of study in which nine healthy volunteers received 20 mg of prednisone before and after four or 14 days of RTV 200 mg BID [Abstract 14]. After four days of RTV, the geometric mean AUC for prednisolone (the active metabolite of prednisone) was increased by 41%. After 14 days, the geometric mean AUC was increased by 30%.

This study was not designed to assess the clinical significance of a 30% to 40% increase in prednisolone concentrations. However, with chronic administration of prednisone and RTV, one could guess that the risk of long-term steroid toxicity might increase modestly. A more important question not addressed here was the pharmacokinetic effect of lower RTV doses of 100 mg QD or BID, which are now much more commonly used in HIVinfected patients.

Synergistic Hepatotoxicity With Rifampin and PIs

As more patients with tuberculosis receive HAART, especially in resourcelimited settings, there is an increasing need for regimens that can be safely administered with rifampin, a cornerstone of TB treatment but a very potent inducer of CYP 3A4. Rifampin is contraindicated with most PIs because it lowers their concentrations considerably. In an attempt to find a boosted PI regimen that could be used with rifampin, investigators from Roche studied the combination of saquinavir/ritonavir 1000/100 mg BID with rifampin 600 mg QD in a group of 28 healthy volunteers [Grange S, et al. Abstract 35)].

Of the 14 subjects who received rifampin for two weeks followed by SQV/RTV, nine developed profound (grade 3-4) increases in hepatic transaminases within a few days of starting SQV/RTV. AST and ALT concentrations of >2000 IU/L were reported, and one volunteer required observation in a medical intensive care unit for one day. Only 2/14 subjects who received SQV/RTV first and then added rifampin developed increased transaminases, and their elevations were less severe (grade 2 or 3). Fortunately, all liver enzyme elevations resolved spontaneously after the drugs were stopped, and there was no evidence of any lasting liver injury.

This study prompted a “Dear Doctor” letter from Roche in the spring, warning providers not to use these three drugs together. However, it was noted at the conference that this combination has been used anecdotally in HIV-infected patients with TB, especially in Europe, with no evidence of hepatotoxicity. The fact that this adverse event occurred in healthy, HIV-seronegative volunteers and not in HIV-infected subjects may be significant. Richard Chaisson and colleagues from Johns Hopkins University have reported an unexpectedly high incidence of reversible hepatotoxicity in HIV-seronegative patients with positive TB skin tests treated with rifampin and pyrazinamide (presented at the 2005 American Thoracic Society Meeting).

Finally, the rifampin analog rifabutin frequently causes grade 3-4 neutropenia and fevers in healthy volunteers, but appears to rarely, if ever, produce the same toxicity in HIV-infected patients [Flexner C, Barditch- Crovo PA. Clin Pharmacol Ther 2003;74: 592]. This is a situation where the immune dysregulation associated with HIV may actually protect patients from some drugrelated toxicities. Caution is certainly warranted when using rifampin in healthy persons participating in drug interaction studies. However, combining rifampin with PIs in HIV-infected patients with TB warrants continued investigation.

Tenofovir and Fosamprenavir The nucleotide analog tenofovir DF (TDF) is not a known inhibitor or inducer of hepatic drug metabolizing enzymes like CYP 3A4. Yet TDF has been reported to reduce concentrations of some coadministered PIs like atazanavir and lopinavir by as much as 25% to 35%. The effect of TDF on the pharmacokinetics of fosamprenavir (FPV) has not been previously evaluated.

Investigators from GlaxoSmithKline administered FPV 1400 mg with RTV 100 or 200 mg QD to 30 healthy volunteers, half of whom also received TDF 300 mg QD [Kurowski M, et al. Abstract 10]. After 14 days, TDF administration did not significantly alter any FPV or RTV PK parameters. The authors recommended that FPV/r and TDF can be administered QD without the need for dose adjustment, although tenofovir plasma concentrations were not measured in this study.

Enfuvirtide Concentrations With the Bioject Delivery System

Enfuvirtide (T20, ENF, Fuzeon) has been an important addition to salvage therapy regimens, but its clinical utility is limited by local skin toxicity, mainly subcutaneous nodules at injection sites. A new needle-free gas-powered injection system is being tested, and is reported to greatly reduce the frequency and magnitude of cutaneous toxicities. However, there has been some concern about the bioequivalence of the new delivery system as compared to syringes.

Researchers from Vancouver measured enfuvirtide plasma concentrations at trough and one hour post-injection in 23 HIVinfected patients before and after switching from syringes to the Biojector [Harris M, et al. Abstract 48]. Median enfuvirtide concentrations did not change with the Biojector, but concentration variability increased, and a few patients had low enfuvirtide trough concentrations with the Biojector. For most subjects, the Biojector system produced equivalent enfuvirtide concentrations, and was associated with a 50% decrease in injection site reactions. In addition, all subjects maintained an undetectable viral load or had a further viral load decrease after switching from needles to the Biojector.

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