TMC125 (etravirine)

Intelence ®

Rob Camp, 11 January 2008

One more step in the ART (r)evolution

Introduction

Etravirine (ETR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that has been studied for use in persons who already harbor mutations to another NNRTI and is the first non-nucleoside to show efficacy after an initial NNRTI failure. The current New Drug Application, and this paper, deal only with Tibotec, the sponsor's, current application for accelerated approval for etravirine (also known as TMC125, brand name Intelence®) among treatment-experienced individuals, based on 24-week data from the DUET studies.

Development of ETR was original and exciting. Although FDA has been encouraging use of combination experimental agents in Ph III studies since the year 2000, Tibotec was the first company to actually do so, with impressive results. The HIV community once again sees Tibotec as setting the bar for the future of HIV research and sees DUET as a protocol to be admired and mimicked where feasible, even between companies.

In the phase III studies, adverse events were generally comparable to placebo, except for rash. The most commonly reported adverse events across all clinical trials include rash, diahrrea, nervous system disorders, nausea and psychiatric disorders (all grades). Hepatic AEs were seen in 5.3% of people, and the most common laboratory abnormalities (grades 3 or 4 treatment emergent) were elevated amylase (7.5%), triglycerides (7%) and total cholesterol (5.8%).

TMC125 is more bioavailable after a meal, and will be recommended to be administered following a meal. The dose to be marketed is 200mg BID (2 x 100mg tablets BID).

Twenty-four week data are available from two studies, DUET-1 and –2, in 1203 patients, all of whom had at least one theoretically active drug (TMC114/r), half of whom had access to both TMC114/r and TMC125. The lack of a public FDA Antiviral Drug Advisory Committee hearing to discuss the implications of approving this first second line NNRTI is regrettable, especially re: what trials to do in the future and how to capture information on populations like women (a miserable 10% of DUET’s numbers). Otherwise, there are no signals pointing to why FDA should not approve Tibotec’s application for accelerated approval of etravirine to treat HIV infection in NNRTI-experienced adults. This recommendation is based on the follow-up studies in section 2 being commenced and successfully completed in a timely fashion.

This paper will discuss the following issues:

1. Executive Summary
2. Crucial post-marketing Studies
3. Pharmacokinetics, population-specific concerns, Dosing & Drug Interactions
4. Safety
5. Resistance
6. Expanded Access
7. Note to FDA and Random Ramblings

Appendix 1 – Random Ramblings

Appendix 2 - Letter to FDA 22 Dec 2004

1.  Executive Summary

In 2008, what would distinguish a new ARV? The goals of therapy for treatment-experienced patients are that it can get you to a viral load <50 copies as well as preventing resistance and maintaining future treatment options. Tolerability, convenience and quality of life are no longer of added value but are primordial in an ARV regimen. A novel drug can be a healthy addition by showing it can work effectively in a resistance-laden population, by having a minimal toxicity burden broken down by gender, race and age, and be reasonably priced.

ETR will be taken as two whitish 100 mg tablets twice a day, totaling 4 pills per day. It should be taken following a(n unspecified type of) meal, which increases absorption by some 100%. Studies looking at a new formulation (200 mg tabs) and once a day PK are in design. This paper only contemplates the 100 mg BID formulation.

People with hepatitis made up 13% of the DUET population. Hepatic AEs and elevated hepatic parameters were more frequent in coinfected patients compared with non-coinfected patients. While TMC125 does not appear to increase hepatic toxicity in patients with hepatitis coinfection, the sponsor needs to do more in this area.

Even fewer participants in the pivotal DUET studies – just 10.5% - were women. The data on women submitted for ETR is substandard in a very substandard category. While it is a disgrace, they are partially making up for it by the GRACE study, but it is hoped that Tibotec designs an ETR-GRACE for future work on women. While it is not comfortable to always ask for GRACE studies after approval, it is the best we have right now. It is hoped that FDA can start to show more teeth and demand women directly in Ph III studies (well, all along development, actually) and prohibit certain post-approval activities (like using women in the ads) or demanding phrases like “NOT STUDIED IN SUFFICIENT NUMBERS OF WOMEN” in all their patient and clinician materials.

The 24-week virologic efficacy of ETR was looked at head-to-head with an optimised regimen (OR) that included DRV/r. Current data support use only in an NNRTI-experienced population in combination with an OR of DRV/r + optimised NRTIs and optional T-20. The label should clearly state that ETR has only been effective in this specific setting, in the presence of a fully active PI.

The safety profile of ETR so far is not alarming, but 25% of patients have reported at least one grade 3 or 4 adverse event.

The serious adverse events collected in the EAP have not been categorized or published to help define the risks of ETR use. This should be done immediately.

ETR is effective in the presence of the two primary mutations (Y181C and K103N). The etravirine resistance-associated mutations (RAMs) are V90I, A98G, L100I, K101E, K101P, V106I, V179D/F, Y181C/I/V, G190A/S. Based on available clinical data, ETR keeps more than 50% of the fairly advanced population (median baseline CD4 < 100) below 50 copies at 24 weeks with less than 3 RAMs, which corresponds to 86% of the population looked at in DUET. This information would be very helpful in the label.

In summary, ETR has advantages -- including an exciting resistance profile -- and disadvantages -- including lack of long-term and population-specific data, and a potentially high price. It has also so far been primarily studied with a fully active PI, which on one hand is extremely useful for those who truly have no other options (the DUET population) but slightly disconcerting for a less experienced population who after first line failure of Sustiva, would like to stay with NNRTIs – alas, the data generated so far is NNRTI+PI. Used properly, it will be a useful addition to the current pharmacopeia. Before full approval is granted, the following studies must be done:

2. Crucial Post-Marketing Studies

FDA should require the following studies to be successfully completed. We heartily support the recent legislation to strengthen FDA's ability to mandate completion of such studies, and to sanction sponsors who fail to meet commitments.

Populations. Should this drug be approved in women? Is there enough data? The sponsors opted for faster approval rather than look for ways to be more inclusive (by specifying target numbers, for example). When will the ETR-GRACE study (70% women) be designed and enrolled? Is there a need to state on the label that potential gender differences are likely to have been missed in women (the sex difference in rashes at this point can not be clarified)? Are liver-challenged people being given a fair shake? Further studies are needed to characterize ETR’s effects in liver-impaired people, and under what circumstances it may be contraindicated. The FDA-approved labeling for etravirine should note the lack of significant data from women and co-infected persons.

Drug-drug interaction/PK studies.  Interaction studies need to be done with antiarryhthmics, anticoagulants, anticonvulsants, calcium channel blockers, antibacterials, immunosuppresants, itraconazole, amphetamine and amphetamine derivatives, hormonal contraceptives, buprenorphine, rifampin, rifapentine, fibrates, ribavirin, fosamprenavir, ergot derivatives, midazolam, triazolam and pegylated interferon. The label must indicate whether PK data are translatable towards women (clarithromycin and paroxetine studies were both 100% men) and co-infected persons. Dispersion, coating and a larger mg tab are all under investigation. QD studies are under way.

And how will ETR work without a PI? Does this need to be looked at?

Long-Term Safety. 

Resistance studies. ETR has shown good response to both the K103N and the Y181C, what about the two together? And there were many people with neither of these two significant mutations who did less well. Which resistance profiles predict response or lack thereof to ETR?  In some cases of resistance, will it not work (more than 3 RAMs)? How should this be explained? What are the signature mutations after the failure of ETR? Larger, more comprehensive, longer-term, real-life studies could help here.

Pediatrics.  No data have been presented yet for pediatric use. There is no formulation yet, however, a 25 mg tablet, compositionally proportional to the 100mg tablet, is being used in the pediatric dose-finding trial. The sponsor’s inclusion of pediatrics in the development process is to be applauded. We expect 24-week results in 2008.

Other studies. A CNS tolerability study in 40 patients – switching from EFV, may be very interesting. QOL data need to be strong. T-20 switch – to EFV + DRV/r, again may be very provoking. Newer studies are of long-term safety rollover studies from DUET and other studies.

3. Pharmacokinetics, Specific Populations, Dosing & Drug Interactions

ETR blood levels decrease by 50% without food - food will be a recommendation. After a meal, more than a snack. High fat or not does not seem to matter.

No dose adjustment will be needed with the following NRTIs –TDF or ddI, the following RTV boosted PIs – ATV, DRV, LPV, SQV, LPV/SQV, or the two IIs – raltegravir or elvitegravir.

Dose adjustments may be required with fosAPV/r and maraviroc.

It is NOT RECOMMENDED to co-administer other NNRTIs with ETR – either EFV or NVP. Also, it is not recommended to take TPV/r or full dose RTV with ETR. At the same time, any unboosted PI is not recommended.

We are encouraged that the sponsor has been able to investigate most of the drugs in the ‘by approval’ list in Appendix 1. They should be published quickly. For the ‘by 6 months’ list, patients need to have the outstanding answers in the first half of 2008.

Gender & race

Would you be confident using this in women? The label should specify that data in women is lacking. Postponing studies in half the human race until after approval is unacceptable in 2008. How might one find women? Where are they hidden? Make a target number. The CRO won’t get paid until they reach that number (by heightening trust and motivation, reaching out to local women’s groups, orchestrating a PR campaign, bringing on additional sites, extending clinic hours).

As for race, no differences were seen, but again, numbers were small (>70% Caucasian in the DUETs). Might we see higher blood levels in blacks like we see with efavirenz?

Other ARVs

In older formulations of both drugs, TMC114/r lowered levels of TMC125 (etravirine) by 35% (no effect of 125 was seen on 114.) A small and short study by Marta Boffito in London presented at CROI 06 (12 weeks) and BHIVA 06 (16 weeks) showed a similar (~30%) decrease in 11 people in a salvage situation. No dose adjustment is deemed needed (Boffito 2006, Jackson 2006).

hr = historical reference

Compared to historical references, these reflect unchanged exposure to DRV and a > 30% reduced exposure to TMC125 (in HIV- studies, a 33-37% change had been seen) (Vingerhoets 2006). So, despite a reduced exposure to TMC125, at week 6, all subjects had achieved at least a 2 log₁₀ decrease in viral load with a median of –2.55; 5/10 and 8/10 had viral load < 40 and 400 copies/mL, respectively. DRV/r and ETR work together, and this small study is a proof of concept (albeit retroactive) for the DUET studies. Tibotec has not done their own direct study. How might ETR work without DRV/r is an interesting question.

The increase of exposure to TMC125 when coadministered with either ATV or ATV/r is considered not to be clinically relevant. However, due to the significant decrease of C_min of ATV when given with TMC125, this combination should only be used if combined with ritonavir

ETR with other PIs (ATV/r, KAL) may be interesting, or even without PIs, to see what a non-50% lowering of blood levels of ETR might do.

Other common drugs

TMC125 is an inducer of CYP3A4, inhibitor of CYP2C9 and 2C19 - all metabolic pathways for oral contraceptives (OC). One study assessed the effect of steady-state TMC125 on the pharmacokinetics (PK) of ethinylestradiol (EE) and norethindrone (NE). 30 HIV- females participated (median age 24 yrs). When combined with TMC125, EE AUC_24h was 122% compared to administration of OC alone; C_max and C_min were 133% and 109%, respectively. AUC_12h, C_max and C_min of NE were 95%, 105% and 78%, respectively, when combined with TMC125 compared to administration of OC alone. The concomitant administration of TMC125 and OC was generally safe and well tolerated. Ten AEs led to trial discontinuation: seven grade 2 rashes, one grade 2 pyrexia, one grade 3 herpes simplex and one grade 2 lymphadenopathy. While “no loss in contraceptive efficacy of OC is expected when TMC125 is coadministered”, it may not be easily tolerated by everyone.

Interaction study done with antacids – no problem.

No dose adjustment needed with pH modifiers, omeprazole, ranitidine, methadone, oral contraceptives, paroxetine, rifabutin, atorvastatin, clarithromycin. An alternative to clarithromycin should be considered.

The dose of sildenafil will need to be to amplified.

With lorazepam, temazepam, etc, no studies are planned.  Their concomitant use is allowed, and no effect is expected. Concomitant use of SSRIs is allowed. There are no interactions with PPIs or H2 antagonists, they are allowed. No reaction is expected with either glitazones or metformin, and they are allowed. No dose adjustment needed for ranitidine. ETR and ketoconazole levels have not been looked at yet.

Many drugs are unknown or still only theoretically allowed. Please see the letter sent in December 2004 re: timelines of when the most common drugs should be concurrently studied (Appendix 2). That much being said, the sponsor has done more than the less-than-minimum normally seen by approval and we hope to see even greater advances with their next compounds, and that they may be looked at as a leader in the field to be emulated (and hopefully surpassed!) by other companies.

4. Safety and side effects

This experienced population, more vulnerable to side effects due to longer treatment history and longer history of having HIV, needs a kind and gentle salvage therapy. In tolerability, ETR + 114/r did generally no worse than the 114/r arm. Tolerability in a late stage drug is hard to judge – discontinuations or lack thereof may not be a reliable marker of tolerability if there is nowhere to go, treatment-wise.

Rashes were successfully treated through in most cases. They are early onset (most frequent in the second week), last some 11 days, and are treated through. The vast majority are of grades 1 or 2 (1.3% gr 3, no gr 4). There was a higher incidence in women, but no difference in severity or treatment discontinuations between sexes. There was no association with baseline CD4 cell count, and no increased risk in patients with a history of NNRTI-related rash. A comparitive chart vs Viramune would be helpful.

Nervous system – headache (9%), dizziness (3%) and somnolence (2%), only grades 1 and 2. Psych disorders reported were low – 13%, mostly grades 1 and 2 – insomnia (6%), depression (3%), anxiety (3%) and sleep disorders (1%). A comparitive chart vs Sustiva would be helpful.

Safety within HBV or HCV co-infected people was similar between arms (with or without DRV/r). More work needs to be done.

There were 8 deaths in the TMC125 arm at wk 24, 15 in the placebo. None of the deaths were considered possibly related to study drug.

Incidence of grade 3 or 4 ALTs and ASTs was higher in the ETR+DRV/r group than in the DRV/r group. In the incidence of observed lab abnormalities, triglycerides, total cholesterol and increased glucose (grades 3 and 4) were higher in the ETR arm.

Better systems are urgently needed to monitor chronic and long-term side effects after drugs are approved. The current adverse events reporting system is voluntary and may miss substantial toxicity. A network of “sentinel practices” to report unusual symptoms might be a viable enhancement to the current inadequate MedWatch system. The need for a better system to detect and track side effects (such as the emergence of lipodystrophy syndrome after the approval of the first protease inhibitors) has long been a major concern for the community.

5. Resistance

In study TMC125-C227, Tibotec showed that ETR was not equal to a PI-based second line regimen in those with NNRTI failure. This does not bode well for when to use ETR - it may not be after first NNRTI failure, but after PI failure after NNRTI failure.

The TMC125 resistance-associated mutations (RAMs) are V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A and G190S. No single identified baseline mutation completely eliminates TMC125 response. The K103N is not a TMC125 RAM and had no negative impact on virologic response to TMC125. In fact, in the presence of the K103N, people on ETR seemed to do better (69% vs 63% <50 at 24 weeks).

Having up to and including 2 TMC125 RAMs kept 59% of the studied population under 50 copies at wk 24.

6. Expanded Access

Expanded access – as of early December, close to 3000 US patients were on EAP of etravirine, similar to the ROW number. We applaud Tibotec for doing a conscientious job with the ETR EAP.

7.             Note to FDA 

While we once again admire the flexibility of all regulatory parties concerned in order to get this drug approved rapidly, the lack of an Antiviral Advisory Committee (AVAC) hearing is troublesome. HIV community groups strongly support public hearings whenever a new molecular entity (NME) application goes to FDA for approval. People with HIV, activists and care providers all benefit from the open discussion that is part of the AVAC hearing process. They are a valuable opportunity for participation and learning.

We hope that FDA takes a more flexible, pro-active role with respect to advisory committee hearings, continuing to use them as often as possible.  We also remind FDA that prompt on-line publication of its interpretation of the dataset is vital, including documentation of safety, statistical, subgroup, and efficacy concerns, and a clear list of required post-marketing studies.

PDUFA IV, reauthorized in September 2007 as part of the FDA Amendments Act (FDAAA) 2007, directs fees towards drug safety for the first time, adding $225 million specifically for this purpose over the next 5 years. We hope to see quick uptake and response as the results come in, and wish FDA all the best in this new endeavour.

To improve the drug development and regulatory processes by facilitating timely access and approval the non-profit Reagan–Udall Foundation was created through the same FDAAA. Its aims will be to modernize product development, accelerate innovation and enhance product safety.

The most critical need for FDA is more funding. The agency suffers from serious scientific deficiencies and is not positioned to meet current or emerging regulatory responsibilities, therefore putting lives at risk. Congress regularly increases FDA's responsibilities without providing adequate increases in funding for staff and resources*.

Although pricing doesn’t fall directly under FDA’s regulatory umbrella, we direct your attention to a proposal by the Fair Pricing Coalition that calls for corporate responsibility in pricing this and other new ARVs (Fair Pricing Coalition 2006). Named patient programs in Europe (similar to compassionate use programs in the US) are being charged more than Sustiva, which will certainly signify a burden for most payers.

The US and European HIV treatment community has been fortunate to have worked closely with Tibotec over the past 4 years. While the process has been far from perfect, it has allowed a sense of collaboration that is seldom achieved with industry, and is a model worth repeating, where community gets direct input into the development process in real time, not post-decision making fanfare. FDA should push this aspect of collaboration more.

The author would like to thank the many members of ATAC's Drug Development Committee (DDC) for their particular insights.

Appendix I - Random ramblings

There has been an increasing impetus to assess the burden of HIV using patient-reported outcomes such as health-related quality of life (HRQL) instruments, particularly in the clinical trial setting. This multidimensional construct defines the subjective understanding of the impact a disease and its treatment have on physical, psychological, and social well-being and functioning. As more effective therapeutic options for HIV infection are developed, interest in health-related quality of life outcomes is further increasing. While we applaud this trend, the use of T-20 was not associated with any worsening of any well-being measurements, something that may need to be looked at more closely.

The community worked hard with Tibotec to keep a subjective investigator-centered analysis of alcohol / drug use from being an exclusion criteria. The current language is more person-friendly, but data regarding drug or alcohol users has not been made public yet.

All HIV-infected subjects should be advised to take the necessary precautions to reduce the risk of transmitting HIV. Although the goal is worthy, why preach safe sex and abstinence in a treatment trial?

The following description applies for lack or loss of treatment response: Plasma HIV-1 RNA greater than 50 copies/mL at or beyond Week 24 that is confirmed by 2 consecutive measurements. Are clinical trials going too fast? Saying that 2 consecutive tests above 50 = failure, is that realistic in this scenario? What is a person with no other treatment options (which is purportedly the case in these Phase III trials) to do?

Appendix 2: Letter to FDA 22 Dec 2004

Antiretroviral Project

Treatment Action Group

611 Broadway St 608

New York, NY 10012

Phone: 212.253.7922

Fax: 212.253.7923

Debra B Birnkrant, MD

Center for Drug Evaluation and Research

Office of New Drugs

Division of Anti-Viral Products (HFD-530)

CRPII/Rm. N414

Food and Drug Administration

5630 Fishers Lane, Rm 1061

Rockville, MD  20852

Fax: 301.827.2523

Dear Dr Birnkrant,

I am writing to follow up on the productive meeting with the CDER staff and ATAC’s Drug Development Committee (DDC) in November 2003. Many things were discussed during this meeting: (please see Bob Huff’s article in Treatment Issues vol. 17 no. 11 at www.gmhc.org/health/treatment/ti/ti1711.html#3, that reviews specifically

·      PK data

·      Drug-drug interaction studies

·      ‘Real life’ study populations

·      Post-marketing research

·      and Long-term side effects (a la sentinel cohorts)).

I am writing solely as a member of the Treatment Action Group to help you think about the first three points - what data needs to be seen with new drugs before approval decisions are made on upcoming drugs.

This letter will focus on pharmacokinetic (PK) issues as they apply to specific populations and drug-drug interaction studies (1), and on further outlining changes we are requesting regarding required or desirable pharmacokinetic and drug-drug interaction data which should be available from sponsors of investigational new drugs (INDs) for treatment of HIV disease and associated complications, either at the time the new drug application (NDA) is submitted, or as part of the suite of required post-marketing studies. 

As discussed a year ago, the community is suggesting that certain data be routinely included in every approval package and be required -- or strongly encouraged – by the FDA of sponsors.  In some cases, e.g., accelerated approval, the FDA may have more leverage than in others.  However, we encourage the FDA to think creatively about strategies for obtaining and requiring the capture of data necessary to better guide clinical care for people living with HIV. Can approval be deterred until the data submitted?

The studies most needed that would help in better defining the toxicity and safety of new drugs, are:

By approval:

• All currently approved ARVs (including AZT, ddI, d4T, 3TC, ABC, efavirenz, nevirapine, tenofovir, indinavir, nelfinavir, fosamprenavir, saquinavir, atazanavir with and without ritonavir, lopinavir/r. They should be conducted in small numbers of HIV+ patients before efficacy data is collected. For example, would the Boehringer Ingelheim BI 1182.51 study have shown the same results in a shorter sub-study - to see that there were some serious interaction issues between tipranavir/r and (all) other PIs?)
• ARVs not yet approved, as soon as there is dosing.
• Methadone
• Hormonal Contraceptives - oral, patch, and topical delivery of progestional and combined estrogen/progestional agents)
• Lipid regulators (statins, fibrates)
• Food and liquid - what kind of food, how much food, water intake

Within 6 months of approval:

• Ribavirin
• Ulcer drugs (H2 receptor antagonists, Proton Pump Inhibitors)
• Certain herbal medications & supplements (Appendix 1 below)
• Antipsychotics, ie, chloroprothixen, zuclopenthixol, haloperidol, etc
• Seizure drugs, ie, anti-epileptics, anti-convulsants
• Erectile dysfunction drugs, ie, sildenafil, tadalafil, vardenafil

Within 12 months of approval:

• Street drugs (ecstasy, methamphetamine, heroin) – these studies can be undertaken safely and legally in The Netherlands, Switzerland, Spain
• TB drugs (rifampin, rifabutin)
• Pegylated interferon
• Cardiac Drugs, ie, amiodaron, disulfiram, verapamil, beta blockers, etc
• Antibacterials, ie, roxythomicin, clindamycin, etc
• Anti-depressants, ie, buproprion, SSRIs, trazodone, TCAs, etc
• Hypnotics, ie, the non-benzodiazepine selective agonists of the GABA-A receptor complex, as well as benzodiazepines, flurazepam, zaleplon, diazepam, etc
• Antihistamines, ie, levocetirizine, loratadine, cetirizine, promethazine, etc
• Anti-fungals, ie, fluconazole, itraconazole, ketoconazole, voriconazole
• Broncho-dilatators
• Immunosuppresants, ie, cyclosporin A
• Antimalarials
• Uricostatics, ie, allopurinol
• Cytotoxic drugs, ie, tamoxifen, paxlitacel, vincristine, etc
• Complementary and alternative medicines. Because the list is extensive, we might suggest starting with the most commonly used according to FDA’s Center for Food Safety and Applied Nutrition (www.cfsan.fda.gov). Appendix 1 lists some very commonly used CAMs seen at a recent PK meeting.

Not enough information is generated on specific sub-populations within the population of HIV patients that may use the drug at time of approval. We reiterate some common points here below, answers to which are needed more so now than ever before:

Specific Populations 

• Gender percentages that more realistically reflect the population in which the drug is studied, ie, in the US there should be at least 30% women in all trials, including phase I and II pharmacokinetic trials.
• Ethnic and racial differences, again to reflect the epidemic itself.
• People with hepatic and renal insufficiency, especially those with HCV and/or HBV co-infection. For patients with mild liver impairment, are dose reductions needed / recommended? Ditto for those with more serious liver problems? Should more visits and laboratory analyses be performed on people with abnormal LFTs at baseline, including those with chronic hepatitis? 
• Pediatrics / Pregnant women data is rarely generated. Bioequivalence is often not demonstrated for a powder / liquid formulation, if there is one. Pediatric formulations need to be devised and studied in both newborns and infants. Most ARVs are defined as Class C for pregnancy; they have unknown placental passage (newborn:mother drug ratio), and often long after full FDA approval, long-term animal carcinogenicity studies are still not done; along with the post-marketing pregnancy registry, ARVs need to be studied and categorized for use in pregnant women.
• Hyperbilirubinemia and other hepatic abnormalities need to be better characterised in drugs to be approved before approval.

There is an overdue role for well-planned and rigorous population PK in Phase III studies. Would the use of therapeutic drug monitoring (TDM) be helpful in managing different patients and patient populations?  Studies to look at re-dosing via TDM in overdosed / underdosed patients need to be addressed. Can TDM be a useful tool in finding a dose that balances efficacy and toxicity?  (2)

Studies in HIV-negative volunteers may provide a more rapid and efficient way of obtaining the in vivo data for two- and three-way drug interactions. [It must be said that there are safety and ethical issues here as well as possible differences between HIV-negative and HIV-infected volunteers. For antiretrovirals likely to be in wide use, we recommend that as many ARV three-way interactions as possible be done before approval.] (3)

We consider that some of these studies, both the PK studies and the population studies, are important enough to somehow bind the marketing rights of a sponsor who does not carry them out. We are interested in further exploring what to do when a company does not offer all the data considered “minimal”, without in any way keeping that drug from someone in a life or death situation. For example, were FDA to demand 30% women in all HIV trials, and another 20% of people with hepatic failure level C, what would happen if that were not achieved? Why would it not be achieved if FDA mandated it? 

There needs to be a regulatory requirement for drug interaction data not to withheld but released early as an issue of public safety. Transparency and better definition need to be the hallmarks of all studies. [We refer to our support of the AMA and the growing association of some 17 scientific journals to publish all studies, both positive and negative and new Open Access initiatives, like the Public Library of Science (www.plos.org).]

Thank you for your anticipated assistance.  The community has been making the same PK / population requests of Industry for many, many years and greatly appreciate the agency’s concern in providing Industry with direction in this regard. Please do not hesitate to contact me with questions or feedback.

Very truly yours,

Rob Camp

Antiretroviral Project Director

Treatment Action Group

Cc: Deputy Director Jeffrey Murray, M.D. HFD-530 301-827-2338 CRPII/Rm. N413

Appendix 1: Complementary and alternative medicines (CAM) (vitamins/minerals, homeopathy, herbal, other) commonly used need to be looked at with ARV therapy. Although we realize that FDA does not regulate CAMs, the interactions of these with ARVs would be very helpful and possibly preventative of complications. A large percentage of people living with HIV use many of the products listed below. A good example of why these products need to be studied is the indinavir/hypericin interaction, where the metabolism of indinavir is speeded up and lower blood levels are the result, with the raised risk of treatment failure and resistance:

Echinacea, Ginseng, Evening primrose oil, Brewer’s yeast, Cannabis, Soy lecithin, Hepatoprotective products, Cat’s claw, Aloe vera, Propolis, Pollen, Bach’s flowers, St John’s wort (hypericin), Garlic supplements, Algae, Kombucha, Supplements such as zinc, selenium, vitamins, melatonin, carnitine, Co-Q, etc (4)

Refs: 1. Identifying metabolic differences in patient groups based on genetic polymorphism, or on other readily identifiable factors, such as age, race, and gender, can aid in interpreting results. 

The effects of an investigational drug on the metabolism of other drugs and the effects of other drugs on an investigational drug’s metabolism should be assessed relatively early in drug development so that the clinical implications of interactions can be assessed as fully as possible in later clinical studies.

- from FDA Guidance for Industry Population Pharmacokinetics, CDER and CBER, Feb1999

Identifying metabolic differences in patient groups based on genetic polymorphisms, or on other readily identifiable factors such as age, race, and gender, could help guide the design of dosimetry studies for such populations groups. This kind of information also will provide improved dosing recommendations in product labeling, facilitating the safe and effective use of a drug by allowing prescribers to anticipate necessary dose adjustments. Indeed, in some cases, understanding how to adjust dose to avoid toxicity may allow the marketing of a drug that would have an unacceptable level of toxicity were its toxicity unpredictable and unpreventable.

Two of the major clinical reasons, as previously mentioned, are (1) to identify all of the major metabolic pathways that affect the drug and its metabolites and (2) to anticipate the effects of the drug on the metabolism of other drugs. With these objectives in mind, an understanding of the metabolic profile of a drug in vitro would be useful prior to the initiation of phase 2 studies and is especially important before phase 3 trials, when a broader population will be studied. This knowledge would permit the efficient design of clinical dose/response, interaction, and special population studies and also would enable adequate attention to be given to patient variability and potential interactions in phase 2 and 3 studies.

1. from FDA Guidance for Industry Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro, CDER and CBER, April 1997, http://www.fda.gov/cder/guidance/clin3.pdf, Issued, Posted 4/8/1997.

2. from FDA Guidance for Industry In Vivo Drug Metabolism / Drug Interaction Studies – Study Design, Data Analysis, and Recommendations for Dosind and Labeling, CDER and CBER, November 1999, http://www.fda.gov/cder/guidance/2635fnl.htm, Issued 11/24/99.

3. Jonathan Schapiro and Terrence Blaschke, personal communications to author during the 5^th International Workshop on Clinical Pharmacology of HIV Therapy, 1-3 March 2004, Rome, I.

4. Partial list compiled from two posters (Meemken, abstr 4.12; Tuset, abstr 4.18) at the 5^th International Workshop on Clinical Pharmacology of HIV Therapy, 1-3 March 2004, Rome, I.

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