One Pill, Once-a-Day, and Other Charms from Lisbon: Update from the 7th International Workshop on the Clinical Pharmacology of HIV Therapy

Hopkins HIV Report 2006 Jul; 18(4):1-5

Charles Flexner, M.D. and Adriana Andrade, M.D.
Johns Hopkins

Lisbon is a European capital visited infrequently by Americans, which is a shame given the physical beauty and charm of this ancient city. In late April, 200 clinical pharmacologists from around the world gathered there for the 7th International Workshop on the Clinical Pharmacology of HIV Therapy. They shared outstanding science, including a number of important reports on the pharmacology of existing and new drugs. Also presented were the first clinical results of studies with the new one pill, once-a-day coformulation of efavirenz (EFV), emtricitabine (FTC), and tenofovir DF (TDF).

One Pill, Once-a-Day

For the past decade, much effort has gone into regimen simplification as a means of improving antiretroviral adherence. This trend has manifested itself most recently with the availability and increasing popularity of the Truvada and Epzicom coformulations. For several years, investigators from Bristol Myers-Squibb and Gilead have been collaborating to develop a coformulation of three drugs: EFV, TDF, and FTC. This endeavor has been fraught with many problems and setbacks, as the final product had to contain 1,100 mg of drug and very little excipient. Three previous coformulations failed because they produced inadequate EFV concentrations in human subjects. However, it now appears that there is a coformulation with acceptable bioequivalence and manufacturing properties. The first results of clinical studies with this single tablet regimen (STR) were presented in Lisbon.

Potential advantages of an antiretroviral STR include added convenience and simplicity for the patient. In addition, a single tablet regimen means that the patient will either take all of their drugs or none, perhaps reducing the risk of taking an incomplete regimen and developing resistance. STR regimens should be matched for pharmacokinetic properties (mainly clearance or half-life of the active drug), and must have appropriate chemical compatibility.

Brian Kearney and colleagues from Gilead presented results of a cross-over trial in which 48 healthy volunteers received either the STR or all three individual components as separate tablets, administered in random order 21 days apart. Thirty-five of the subjects were women and 13 were men; 90% were Hispanic. Pharmacokinetic analysis at the end of the study (see Table, p 2) indicated that the new STR met bioequivalence comparisons for all three drugs. Two subjects became pregnant during the study, but there were no other significant side effects noted.

The size of the new STR tablet is slightly larger than that of the current Truvada tablet (see Figure), so this may be a problem for patients who have difficulty swallowing large tablets. However, it is likely that many patients currently taking these three drugs as separate tablets will wish to switch to the single tablet. This may also be an attractive option for treatment-naïve patients desiring a simple regimen that they can take once a day. The true benefits of this new product remain to be determined, but most will see this as a major advance in the quest for unobtrusive, long-term control of HIV infection.

Editor’s Note – As this issue of the HHR was going to print the FDA gave approval to this combination of EFV, TDF, and FTC under the brand name Atripla. Full prescribing information may be found on the web at: http://www.fda.gov/cder/foi/label/2006/021937lbl.pdf.

Figure. Comparison of the size of the new EFV/TDF/FTC single tablet regimen (on the right) to current EFV 600 mg tablet and Truvada tablet (on the left). Photograph reproduced with the permission of Bristol-Myers-Squibb.

Fixed-Dose Formulations: The Down Side

Although providers and patients usually see combined, fixed-dose formulations as a good thing, Rafaella L’homme and colleagues presented a study that emphasized the down side of such tablets [Abstract 2]. This group determined steady-state concentrations of nevirapine (NVP) in 71 Malawian and 56 Zambian children who were receiving the Triomune fixed-dose combination of generic NVP, lamivudine (3TC), and stavudine (d4T). This tablet comes in only one size (200 mg of NVP, 150 mg of 3TC, and 40 mg of d4T, given twice daily). Young children in resource-poor countries are given one-quarter, one-half, or three-quarters of a tablet twice a day depending on body size.

When NVP concentrations were measured in these children (age range 3 months to 16 years), 18% had NVP trough concentrations below the target of 3.0 mg/mL, which is considered subtherapeutic in some European countries. Most of the underdosed children were small, and were receiving the one-quarter or one-half tablet dose. Children closer to adult size had close to adult concentrations of NVP.

This study makes the point that fixed-dose combinations of some drugs may not be appropriate for pediatric patients. It was also pointed out that children under the age of two years may have a hard time swallowing tablets of any size, and that crushing fixed-dose tablets may not solve the problem because of altered bioavailability of the crushed tablet. This study reminds us that, when it comes to antiretrovirals, one size will never fit all.

A Skin Test for Abacavir Hypersensitivity?

The abacavir (ABC) hypersensitivity reaction (HSR) is an uncommon but life- threatening side effect of an otherwise well- tolerated nucleoside analog. In fact, concern about HSR has led many providers to avoid the Epzicom coformulation, which contains ABC and 3TC.

An important problem in managing HSR is the difficulty of distinguishing true hypersensitivity, which often includes fever, abdominal symptoms, and rash, from nonspecific symptoms that may be mistaken for HSR. For example, patients started on EFV and Epzicom frequently develop rash, which may be mistakenly diagnosed as HSR, although a less serious EFV rash is far more likely. Patients on ABC who develop a fever may also be taken off the drug and labeled as having HSR, even when no other symptoms are present.

Elizabeth Phillips and colleagues in Vancouver have developed a skin test for ABC hypersensitivity. They evaluated this product in 42 patients with a previous diagnosis of HSR [Abstract 33]. Patients were tested with dermal patches containing 0%, 1%, or 10% ABC, and results were read after 24 hours. More than half of these patients (22/42) had negative patch tests. Patch test negative patients often did not fit the classic HSR syndrome: they were more likely to have onset of symptoms very early (<3 days) or late (>21 days) after starting ABC, usually had only 1 or 2 symptoms of HSR, and only 9% were HLA B*5701 positive, compared to 100% of patch test positive patients.

The authors concluded that HSR is frequently misdiagnosed, resulting in unnecessary cessation of ABC. Six of the patch test negative patients have now been rechallenged with ABC, and all have done well with no evidence of HSR. The main drawback of this test is that it only has diagnostic utility in patients already exposed to ABC, since it relies on a delayed-type hypersensitivity (DTH) skin reaction that requires prior exposure to the antigen.

How Protease Inhibitors Increase Tenofovir Concentrations

It has been known for several years that tenofovir concentrations increase by 20-30% in patients receiving some HIV protease inhibitors, including lopinavir/ ritonavir (LPV/r) and atazanavir (ATV). The mechanism for this interaction has been a mystery, since tenofovir is entirely excreted through the kidney. LPV and ATV inhibit hepatic drug metabolizing enzymes like cytochrome P450 3A4 but are not known to alter the renal excretion of other drugs.

Investigators from Gilead carried out a series of in vitro experiments to examine the potential role for drug transport proteins in this interaction [AS Ray, et al. Abstract 39]. They determined that TDF uptake into renal tubular cells in vitro is mediated by two transport proteins called organic anion transporters-1 and -3 (OAT1 and OAT3). Efflux of TDF out of the renal tubular cell and into the urine is mediated by multidrug resistance protein-4 (MRP-4). LPV and ritonavir (RTV) inhibit tenofovir uptake mediated by OAT3 and could therefore reduce renal excretion of this drug. The PIs had no effect on MRP-4, so they would not be expected to increase tenofovir accumulation in renal tubular cells, which might cause greater nephrotoxicity.

A second study examined the transport of tenofovir across intestinal epithelial (CaCo) cells [AS Ray, et al. Abstract 49]. The tenofovir prodrug TDF was found to be a substrate for the intestinal efflux transporter p-glycoprotein (P-gp). ATV, LPV, and RTV all inhibited P-gp mediated efflux of TDF. If P-gp plays an important role in limiting absorption of TDF (by effluxing the drug back into the intestinal lumen), then P-gp inhibition by PIs could improve systemic bioavailability of tenofovir by allowing more drug to enter the circulation. This is consistent with clinical data showing that the main affect of PIs is on tenofovir bioavailability, not clearance.

Although these data are strictly from experimental cell lines, this model better explains the interaction between TDF and PIs than any other previously proposed.

No Interaction Between Tipranavir and Maraviroc

An important effect of the new HIV protease inhibitor tipranavir (TPV) is induction of the clearance of other drugs and a decrease in their concentrations. Specifically, TPV reduces LPV, amprenavir (APV), and saquinavir (SQV) concentrations by more than 50%, even when boosted with RTV, so TPV cannot be coadministered with these PIs. It has been assumed that this interaction mainly reflects induction of hepatic cytochrome P450 3A4 (CYP3A4), but TPV’s effect on other antiretrovirals that are CYP3A4 substrates has not been examined.

Maraviroc is a promising new CCR5 antagonist (reviewed by Shepherd J and Quinn T, HHR 2004; 16[4]:1). It is also a CYP3A4 substrate. Investigators from Pfizer examined what would happen to maraviroc concentrations if this drug was combined with tipranavir, as might occur in heavily treatment-experienced patients [S Abel, et al. Abstract 77]. Twelve healthy volunteers received maraviroc at the standard dose of 150 mg bid and added TPV/r at the standard dose of 500 mg/200 mg bid for 14 days. At the end of the combination period, maraviroc concentrations were unchanged except for a slight increase in trough concentrations.

This study indicates that TPV will not inevitably reduce the concentrations of all coadministered CYP3A4 substrates. This is good news for the future use of TPV/r in combination with drugs like maraviroc. The explanation for the lack of interaction is that TPV/r acts principally as an inducer of intestinal p-glycoprotein (P-gp) but as an inhibitor of CYP3A4. The bioavailability of PIs that are P-gp substrates, like SQV, APV, and possibly RTV, is therefore greatly reduced in the presence of TPV, because Pgp prevents absorption of the PIs. However, concentrations of drugs that are CYP3A4 substrates but not P-gp substrates, as presumably would be the case for maraviroc, would be unaffected or increased by TPV/r.

Pharmacology of HIV Integrase Inhibitors: Peak, Trough, or AUC?

HIV integrase inhibitors are perhaps the most promising new class of antiretroviral agents, given the potent suppression of viral load seen with the three agents tested thus far in monotherapy studies. One of these agents, GS-9137, which is being developed by Gilead, was the subject of a detailed pharmacokinetic/pharmacodynamic (PK/PD) analysis designed to determine which PK properties drive the antiviral benefit.

Brian Kearney and colleagues presented data from 40 treatment-naïve and treatment experienced patients treated with GS-9137 alone for 10 days [Abstract 73]. These subjects received one of five different regimens that produced very different peak and trough concentrations: 800 mg qd; 200, 400 or 800 mg bid; or 50 mg qd with 100 mg of ritonavir (data taken from a study discussed in detail by Flexner C, HHR 2006; 18[2]:10).

When a variety of pharmacokinetic parameters were compared to the degree of viral suppression in individual patients, it appeared that virologic response was driven by the trough concentration, with greater suppression associated with the higher troughs [Abstract 73]. Peak concentration and area-under the concentration-time curve (AUC) were not strongly correlated with efficacy.

This is an important finding, because it indicates that the greatest long-term benefit from this drug is likely to derive from regimens producing high troughs at the end of a dosing interval. This would favor ritonavir-boosting of this drug, which is a CYP3A4 substrate, or more frequent administration of unboosted drug (bid rather than qd). Results of this analysis were used by Gilead to choose regimens for their Phase 2 studies.

This study confirms what many pharmacologists have believed about the dosing of antiretroviral drugs: that it is more important to maintain the highest possible concentration of a drug in the plasma for the longest period of time, and that higher peak concentrations may increase the risk of toxicity but do not contribute to antiviral benefit [Flexner and Piscitelli, AIDS. 2002 Mar;16 Suppl 1:S1-3]. This also provides a concrete example of the value of PK/PD analysis early in antiretroviral drug development.

Differences in Drug Toxicity, Adherence and Drug Interactions in the Developing World

Gary Maartens from Cape Town University presented a comprehensive review outlining the main differences in antiretroviral-induced toxicities, management of drug interactions, and adherence in the developed and developing world. He started by noting that although there has been a massive expansion of antiretroviral access in resource-poor settings, only a limited number of drugs are available in the majority of these places. This limitation complicates patient management, as there are few alternatives to overcome common occurrences such as drug-induced toxicity.

For example, the combination of d4T, 3TC, and NVP is one of the first line regimens recommended by the WHO for the treatment of patients with AIDS in resource-poor settings. However, a recent study in South Africa suggested that toxicity-driven regimen changes were most commonly caused by d4T-induced adverse events [Boulle A, et al. Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13:abstract no. 66]. Even more concerning was the report of higher rates of symptomatic hyperlactatemia and lactic acidosis in that study population compared to rates previously described in developed countries. The authors reported that rates of hyperlactatemia and lactic acidosis were as high as 70% in women above 75 kg, which is of concern, since 70% of patients starting antiretroviral therapy in this setting are women. The reasons for higher rates of d4T-induced toxicity are unknown but could be driven by a number of factors, including genetic polymorphisms and the surprisingly high prevalence of obesity among urban South African women. These findings reinforce the importance of conducting studies in resource-poor settings, to continue to assess safety and efficacy of antiretroviral therapy, and to strengthen pharmacovigilance in these populations. It remains to be seen whether these findings will influence public policy and lead to changes in the current WHO recommendations for first line regimens.

Dr. Maartens reminded us that drug scarcity in resource-poor settings is not confined to antiretroviral therapy, but also extends to agents used in the treatment of AIDS-associated co-morbidities. For instance, anticonvulsants such as phenytoin and carbamazepine are commonly available but are potent inducers of cytochrome P450 3A4 (CYP3A4), the main metabolic pathway shared by most PIs and NNRTIs. Co-administration of these drugs with PIs and NNRTIs can significantly lower antiretroviral plasma concentrations and potentially lead to resistance and treatment failure. There are new anticonvulsant drugs that bypass the CYP450 metabolic pathway, but these drugs are costly and not readily available in resource-poor settings.

Treatment of tuberculosis also represents a challenge. Rifampin is a potent CYP3A4 inducer and thus not recommended for concomitant use with most PIs and NNRTIs. Rifabutin, a rifamycin with less potent inducing effects, is not available or affordable in most resource-limited settings, leaving clinicians to cope with significant drug interactions. There are a number of other agents, such as antimalarials, antifungals, antibiotics and traditional medications, that can also affect the metabolism of antiretroviral drugs.

Finally, Dr. Maartens briefly reviewed topics relevant to adherence to antiretroviral therapy in resource-poor settings. He described the results of a recent study conducted in South Africa showing an association between higher adherence rates and improved survival [Nachega J, et al. J Acquir Immune Defic Syndr. 2006 Dec 1;43 Suppl 1:S127-33]. The authors also reported that adherence rates between 95-100% were associated with a higher proportion of patients having undetectable viral loads (<400 c/mL). These results are similar to what has been described in the developed word and reinforce the need for randomized clinical trials to study practical interventions for improving and maintaining adherence in these settings.

Significant progress has been made in the availability of antiretroviral drugs for resource-poor countries. Now that HIV treatment is available in many of these countries, it is important to understand population differences that could affect the safety and efficacy of these drugs. It is also crucial that clinicians understand the basic principles of drug metabolism, since a number of drugs available in these settings share metabolic pathways with PIs and NNRTIs. Finally, the importance of adherence must be reinforced in resource- poor settings, where antiretroviral availability is limited and durability of the first regimen is crucial for prolonged viral suppression.

2006-07-10
HHR-2006-07-02

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