written by Jules Levin, NATAP
Abbott Labs held a meeting at their headquarters in Abbott Park, Ill. on Thursday October 15 to discuss the problems associated with Norvir capsules and future plans for Norvir and ABT-378. It was a relatively large meeting as about 50 community representatives attended from various places including the US, Canada, Western Europe, and South America. Also in attendance were about 20 Abbott employees including representatives from marketing, clinical research, manufacturing, and community affairs. We arrived about 12:30 and were met by a buffet to my liking of lasagna, salad, a bean salad, and a must for me of diet iced tea. I prefer Snapple diet iced tea because I have a sugar problem and because their label says they use filtered water.
The meeting was opened about 1pm by Rick Moser of Abbott public affairs. He talked about how Abbott as a company and its researchers who had discovered and developed Norvir were pleased that they could contribute significant treatment advances for HIV. And, that they were very very disappointed and disturbed by the developments with Norvir. I raised my hand and said that people taking Norvir were also very concerned, upset and disturbed by this development.
Dr Eugene Sun, a senior clinical researcher at Abbott, adrressed the audience next. He has played a leading role in developing Norvir after its approval by the FDA. He started by describing the problem. As you may have already heard, crystals formed in the semi-liquid formualtion of ritonavir preventing ritonavir from being adequately soluble. The drug has to be soluble to be fully bioavailable. I don't think I know how to adequately define crystalization except to use some of the language used at this meeting saying that it's when a compound or element takes another form that is not as soluble. The appearance of these crystals was very sudden and was discovered during the process of screening drug before it is released to the public.
The FDA requires close supervision of screening of drugs after the manufacturing process and before its released to the public. Abbott assured us, as I have heard them a number of times before, that Norvir capsules released to the public prior to this problem was properly screened, unaffected by the crystalization, and was safe and fully effective. This problem of crystalization effected the capsules but not the Norvir liquid if the liquid is stored properly (68-77 degrees fahrenheit). The storage recommendations for the liquid are discussed below. They repeated a number of times that all capsules released to the public prior to the problem are not effected by this problem, because the audience raised this question several times. Dr Sun called ritonavir prior to crystalization Form One Ritonavir and ritonavir after the crystalization as Form Two Ritonavir. He said we will never be able to go back to Form One Ritonavir. We are now in a Form Two world. At this point the discussion took a science-fiction like turn.
As you probably already know, as a result of this problem, Norvir capsules have been removed from the market. Inventory of Norvir capsules that were available through wholesalers prior to the problem is still available but running out. Some pharmacies still have a supply of capsules but other pharmacies do not have any capsules. When this pre-existing inventory is used up, there will be no more capsules available. But, the liquid formulation of Norvir is still available and being produced by Abbott in sufficient quantity to supply the need for Norvir worlwide. . They said that they have switched over their manufacturing facilities to only producing the liquid. All persons using Norvir are being advised to switch to the liquid form.
The problem is that the liquid form has a very bad taste. Some people have difficulty tolerating the taste of the liquid. The liquid form of Norvir was the first available form of Norvir. Early studies of Norvir which were used for its FDA approval used the liquid form. As well, Norvir was approved simultaneously by the FDA for children and adults. As a result, there has been much experience using the liquid. Doctors and researchers have accumulated many dietary suggestions for improving the taste and tolerability of the liquid. The NATAP web site <www.natap.org> has two large grid charts of dietary suggestions for adults and children compliled by doctors and researchers (click here to see charts).
Planning To Replace the Old Norvir Capsule with the Soft Elastic Capsule Replacing (5-6 months or longer). Abbott has been developing a soft elastic capsule (SEC) which they had been working on for a while previous to the occurrence of the capsule problem. Unfortunately, its development has been slowed because attention and resources were diverted to the capsule problem. They have re-focused their efforts to the process of developing the SEC for consumers. Abbott told us their plan is to substitute the SEC for the capsule. They are in the process of refining the SEC. They are designing this capsule for the purposes of being able to use Form Two Ritonavir. So, the crystalization problem is not supposed to be an issue.
Abbott said they are working closely with the FDA. The FDA has to be satisfied that the SEC is bio-equivalent with the old capsule and that antiviral activity is equal. The FDA must be satisfied with the SEC's bioavailability, stability and shelf-life. To satisfy the FDA, Abbott is conducting studies for bio-equivalence and a phase I study in healthy volunteers. Of course, Dr Sun was asked by a number of people in the audience when the SEC would actually be available for consumers. The nature of ongoing discussions with the FDA makes it difficult to give a specific date. He did say the SEC will not be available in 1998. It may be 5-6 months or longer before the SEC may be commercially available. It is my speculation based on my impressions from this meeting that if all goes well with the SEC it may be available during the Spring of 1999. Abbott officials repeated several times, including in personal talks I had with several key officials, that they felt very confident they would be successful in bringing the SEC to the public. But, the SEC will have to pass clinical and manufacturing testing before reaching the public. Abbott officials also said they are trying to improve the taste of the liquid form.
A question was raised about the new recommendation for storage of the Norvir liquid. Previous to this problem the storage recommendations for the liquid were different. It is now recommended that the liquid be stored at between 68 to 77 degress. Needless to say this can be challenging for certain individuals. Abbott was asked why the range of 68-77 was so narrow and if there was flexibility. In other words, is 60 or 82 degrees acceptable. Dr Sun said the reason they narrowed the storage recommendations is because it was the only temperatures they could recommend for which they felt they could assure crystalization would not occur. Dr Sun was asked if crystalization had ever occurred with the liquid. He said that there were a few isolated instances of such an occurrence. He said you can actually see if crystalization occurs in the liquid by holding it up and looking into the bottle. It was said that refrigeration of the liquid may encourage crystalization. I don't think it's an official recommendation from Abbott, but in discussion at the meeting it was stated that shaking the bottle or keeping it at room temperature might make the crystals dissolve back into the solution. And again by looking into the botle you can observe if the crystals are still present.
Crystalization Expert. Dr Steve Byrn from Purdue University is a scientist expert in the field of crystalization. He addressed the audience about crystalization, polymorphisms, and a similar problem that happened to Glaxo Wellcome with Zantac. He said a slight reduction in solubility would not be a major concern but the problem is that Form One Ritonavir was twice as soluble as Form 2. He said different polymorphisms can have different solubility with drugs in general. He defined a polymorphism as the ability of any element or compound to crystalize as more than 1 distinct species of the compound.. He said crystalization is more likely to occur when a drug is in a liquid or soft-gel form than when it is in a solid form. Nonetheless, it is very unlikely to occur. Dr Byrn described a similar problem Glaxo Welcome had with Zantac. A Form Two Zantac emerged which they in turn patented, as Abbott has patented Form Two Ritonavir.
Manufacturing Efforts To Salvage Norvir Capsules. Steve Lichter, a manufacturing official from Abbott, discussed the efforts by Abbott to fix the situation. He stated the "Imperatives" from senior management at Abbott given to Abbott staff teams assigned to this problem. They included--
He went on to describe the attempts made to try and fix the problem. Abbott's attempts included cleaning the manufacturing lines for Norvir, reconditioning manufacturing lines, installing new facilities. Lichter said Abbott invested several million dollars to build new manufacturing facilities but failed. Apparently, they decided the emergence of crystals was not preventable and it would be impossible to manufacture ritonavir in the old form. At this point they decided to discontinue attempts to rescur Norvir capsules and they moved to a committment to replace the old capsules with the SEC.
They still do not know why this problem occurred. My impression from listening to Professor Byrn is that this may be a natural phenomenon they can spontaneously occur. Alternately, it may have occured for any one of several other reasons. I think Abbott officials said 70,000 people worldwide are using ritonavir and 100% of their manufacturing capacity is devoted now to producing the liquid.
Top Chasers To Improve Norvir Liquid Taste. Representatives from the marketing department led a discussion about a recent consumer survey that Abbott conducted through a survey company to elicit which dietary suggestions might be the best at improving the taste problems of taking the Norvir liquid. The survey was recently completed and the "Top Chasers" as reported by the consumers they tested reported to be in order--
1. Nutella brand hazelnut spread on graham crackers--a fudge-like chocolate
2. Riesen Chocolate Chews-- made by Nestle's
3. Oats N Honey Crunch Granola Bar
4. Toast Crackers with Peanut Butter--these are the round small peanutt butter sandwiches
In general, these foods fall in line with other dietary suggestions that chocolate and peanut butter are among the best if not the best at masking the taste of the liquid. Again, the NATAP web site <www.natap.org> has two extensive grid charts listing many dietary suggestions compiled by doctors and researchers affiliated with the adult and pediatric ACTG (click here to see charts). It is recommended that you should not mix the ritonavir liquid with other liquids and take them together. That is because the entire mixture will taste bad, and instead of having a small amount of liquid that tasts bad you will have a larger amount of liquid that tastes bad. It is recommended that you take something to counter the taste of liquid Norvir before and something after taking the liquid--thus the terminology "top chasers".
Abbott is unable to endorse alternate approaches to administering Norvir liquid because they are not FDA approved and studies have not been conducted to establish their effectiveness. Several of these alternative methods were raised by people in the audience at the meeting. It was suggested that some people may be using an eyedropper to place Norvir liquid in capsules. Abbott said they could not recommend this because they don't know how untested capsules would interact with the absorption of the liquid into the human.
ABT-378. As some of you know, ABT-378 is a new protease inhibitor being developed by Abbott Labs. The first data on its use in HIV infected individuals was reported at the World Intl AIDS Conference in Geneva. In a small study of treatment-naive individuals, an interim 24 week report showed 91% had <400 copies/ml. It appears ABT-378 is very potent, more tolerable than ritonavir, has a different resistance profile than other protease inhibitors, and will be dosed twice daily. ABT-378 may be effective in suppressing protease resistant virus for individuals who have developed resistance to protease inhibitors. Combining a small amount of ritonavir with ABT-378 greatly enhances the pharmacokinetics of ABT-378. Combining ritonavir in a smaller than usually taken amount with ABT-378 results in greatly increased blood levels of ABT-378 meaning higher levels of AUC and Cmin. It is hoped that this characteristic will increase the potency or antiviral activity of ABT-378, and make it more difficult to develop resistance to ABT-378. It is also hoped that the increased blood levels and different resistantce profile will both contribute to ABT-378 suppressing protease resistant virus for individuals who've failed PI therapy. As you know, for a number of reasons many people have resistance to Pis and other available drugs. There is a desperate need for a protease inhibitor or any therapy that can be effective in suppressing HIV resistant to available drugs.
It is hoped that ABT-378 may address this need. A small study is ongoing in which participants who failed a PI are receiving ABT-378/ritonavir with nevirapine+a new NRTI(s). Until the results of this study are available it remains uncertain whether or not ABT-378 will be effective in suppressing PI resistant virus. Large so-called pivitol studies used for submission to the FDA for approval are expected to begin in 1999. Based on that start time, results of those studies are expected in 2000.
Abbott said they will continue with ongoing commincations with the HIV community regarding future developments. I encourage you to contact NATAP with any questions or comments. If you would like NATAP to furnish intensified communications about the situation please let us know. NATAP's toll-free number is 1-888-26-NATAP. The regular tel number is 212 219-0106.