show reduced serum levels under this test condition. The fact that erythromycin stearate is dosed at times clearly not recommended by our product literature makes the reason for the difference in serum levels patently obvious. The last page of this study provides adequate opportunity to point out that the study was conducted with this dosage administration bias. The second paragraph indicates that this is a commonly occurring clinical setting. Numerous references are made to the fact that the medication was given immediately after a meal, but none mention that this is not the recommended dosage schedule for Erythrocin Stearate Filmtab. STUDY CS NO. 077 This study is essentially a repeat of CS #071 with the exception that both Erythrocin Stearate Filmtab and Erythromycin Base Filmtab are included in the comparison to E-Mycin Tablets. Again, the same deficiencies exist in this study. As we have previously stated, both the Abbott products are to be taken under fasting conditions, not immediately following meals. Comparisons between any studies must be made cautiously in trying to assess the comparability of drug products. However, we are impressed with the great differences in the shape of the serum curves presented for E-Mycin in Study CS#071 and CS#077. They suggest to us that there must be great variability in individual serum levels. However, since only average values are given, this can only be speculated. Some differences at specific sampling times are shown below: The serum levels reported for Erythrocin Stearate Filmtab in studies CS #071 and CS#077 are low for the reasons discussed above. Our product enclosure, in addition to specifying the proper administration time also indicates that peak serum levels of at least 0.6 mcg./ml. are obtained. (See enclosed insert.) Since this insert is FDA approved, it must be obvious that our data must support this figure. The actual levels are consistently above the 0.6 mcg./ml. figure. In Upjohn Study CS #071 the highest level reported for Erythrocin Stearate is 0.44 mcg/ml. (61 hours) and in Study_CS#077 only two sampling periods (60 and 61 hours) show levels of 0.6 mcg./ml. or greater. Such inconsistencies should alert the careful reviewer that some deviation from the recommended use of the drug has occurred. Finally good serum levels are seen with the Abbott Erythromycin Base Filmtab. (See Studies #72-9 and #72-82.) SUMMARY I hope the above comments will be helpful. They appear to follow a repeating pattern at this time. It should be obvious that bioavailability studies can be designed to show any product at advantage over some other product if sampling times or protocol conditions (meals, dosing times, blood sampling times, etc.) are adjusted to show the competitive product at its greatest disadvantage and the product to be promoted at its optimum. If he promotional use of bioavailability studies continues along these lines, we would expect that the credibility of bioavailability information will eventually be eroded and be considered meaningless. ABBOTT INTEROFFICE CORRESPONDENCE To: Mr. M. J. Henrichs, D-309 (NC) The following may be used in commenting on the above two Upjohn studies. Bioavailability information on a pharmaceutical product can be illustrated in a concise and graphic manner by presenting the average serum drug level data obtained after single or multiple dose drug administration. However, there are some serious practical limitations to these data and its applicability to clini cal practice that should be recognized in judging the information. This can best be demonstrated by reviewing E-Mycin protocols CS #037 and CS #056. CS No. 037.-When the dosage forms are prepared from different erythromycins or possess different drug release patterns, it is imperative that the bioavailability protocol fully characterize each product in the study. Study CS #037 employs three different erythromycins (erythromycin base, Upjohn; erythromycin ethylsuccinate, Abbott, and erythromycin ethylcarbonate, Lilly) with different solubilities, different resistance to gastric acid and different absorption characteristics. Erythrocin® Ethylsuccinate Suspensions are rapidly absorbed and generally achieve peak serum drug levels in one-half hour, before the first blood sample was drawn in this study. This means that the peak heights for the blood serum levels were missed. Since peak heighfs tend to characterize the curve and have a significant impact on the area under the curve, a study that is designed to miss the peak heights cannot honestly reflect the performance of that drug. (Area under the curve is a measure of the total amount of drug absorbed.) Of more major and serious concern, however, is the fact that the Abbott Erythrocin Ethylsuccinate Granules were improperly dosed. Our product literature clearly states under "Dosage and Administration": "Adults: 400 mg. erythromycin ethylsuccinate every six hours is the usual dose. . . . If twice a day dosage is desired in either adults or children, one-half of the total daily dose may be given every 12 hours, one hour before meals." Therefore, the proper does of hte Abbott product should have been 800 mg. This would be the recommended dose equivalent to 500 mg. of the Upjohn product. This also explains the unusual dose of the Abbott product used in this study. Twelve and one-half ml. (21⁄2 teaspoonsful) were dosed. Because of the following equivalencies, the product is formulated to provide 200 mg. per teaspoonful. The proper dose should have been four teaspoonsful. Erythromycin base: 125 mg. equivalent to 250 mg, equivalent to 500 mg. equivalent to Erythromycin Ethylsuccinate 200 mg. 400 mg. 800 mg. The liquid suspension products of Erythrocin Ethylsuccinate have shown better clinical acceptance by pediatric patients than coated erythromycin tablets. A large tablet is not an acceptable dosage form for small children. The Upjohn tablet cannot be chewed or crushed for smaller children. E-mycin is an entericcoated tablet. That is, it is coated with a special material that protects the erythromycin base from rapid destruction by the gastric acid. The table does not disintegrate and make the erythromycin base available for absorption until after the tablet reaches the small intestine (where the environment is alkaline and will not destroy the erythromycin). In contrast, erythromycin ethylsuccinate is more resistant to gastric acid destruction and does not require the special enteric protection. Because E-mycin tablets must wait until they leave the stomach to release the erythromycin base, the absorption of the drug is significantly delayed. This is clearly seen in Study CS #037. The blood levels for Emycin do not peak until three hours after the dose is taken. The Abbott product peaks within one-half hour, providing more immediate serum levels. Although there is some danger in comparing bioavailability studies done at different times and under different protocols, it is worthwhile to note the average peak serum levels and area under the curve obtained in a recent Abbott study on erythromycin ethylsuccinate, given at the proper 800 mg. dose. Rather than the value of 1.00 mcg./ml. reported in CS #037, this level of 2.10 mcg./ml. can be roughly compared to the E-mycin value of 1.37 meg./ml. Remember that considerable caution must be exercised in trying to compare values obtained in different studies. CS No. 056.-In this study unequal doses were utilized with a "priming" dose being given for the Upjohn product. Subjects receiving a double dose (priming dose) would be expected to yield higher blood levels. The priming dose is recommended in the Upjohn enclosure because of the unrealibility of the entericcoated tablet. The Abbott Erythrocin® Stearate Filmtab® is not an enteric-coated tablet. Hence, like the erythromycin ethylsuccinate granules, it will give earlier peak blood levels than will the E-mycin enteric-coated tablet. Erythromycin stearate is not as susceptible to acid destruction as is erythromycin base. Because of this fact and our formulation techniques, the Abbott tablet does not need to be enteric coated. Comparative bioavailability studies should be done using the same dose under similar study conditions. Bioavailability studies are not the same as clinical studies and the comparison of products at their clinical doses implies that the products with the highest doses are clinically the most efficacious. The need for a "priming" dose with the E-mycin tablet is stated in the 1974 Physicians' Desk Reference (PDR), product information section: "Adults: 250 mg. four times daily is the usual dose. An initial dose of 500 mg. is suggested to assure adequate and significant blood levels from the first dose and to eliminate variability of absorption which is sometimes associated with enteric coated preparations." The priming dose represents extra medication costs to the patient. A bioavailability study conducted in our laboratories showed enteric coated E-mycin tablets have erratic absorption and 7 of 22 subjects (or about one-third) had no measurable drug levels for the first six hours. When bioavailability information is presented as average values, it masks the individuals differences and subjects with no levels are not apparent. This study does not indicate what range of values make up these average values or if there were individual sub'jects with unmeasurable blood levels. The protocol used in CS #056 was designed for an enteric coated product, so the serum level curve of Erythrocin Filmtab was inadequate characterized. Erythrocin Filmtab usually will achieve peak serum levels one to two hours earlier than enteric coated E-mycin tablets. Serum samples were not collected where Erythrocin Filmtab normally achieves its peak serum levels. As discussed under CS #037, the blood level curve for the Abbott tablet is not properly characterized under these conditions. SUMMARY When bioavailability information is provided in this pseudotechnical manner, it is not fully recognized as advertisement. The studies can be designed to be technically biased. This is clearly shown when one compares CS #037 and CS #056. The comparison in CS #037 was not done at recommended doses, so the Abbott suspension (granules) appeared to yield inferior drug serum levels. In CS #056, the reader may be unaware of the erratic drug absorption characteristic of the E-mycin tablet. In this study, tablets with different availability characteristics and different reliability (enteric versus non-enteric tablets) were tested at different dosing intervals (every six hours and every twelve hours) and with and without priming doses (E-mycin and Erythrocin). The study was designed to catch the peak heights for E-mycin and to miss the peak heights for Erythrocin. Given these variables, we do not feel that this study is a valid comparison of anything except differences between E-mycin when dosed every six hours versus every twelve hours. Since Abbott studies do not employ the extra priming doses, we have no laboratory data that would be comparable to the Upjohn study. However, in studies where we have given 500 mg. of erythromycin stearate in a single dose (as part of a twice daily administration schedule), we have obtained average peak levels ranging from 1.1 to 1.9 mcg./ml. (mean of four studies, 1.57). This can roughly be compared to the first 500 mg. dose of E-mycin given in Treatment B. There E-mycin gave an average peak level of 1.04, before the second dose was given at six hours. We are enclosing a copy of the previously cited article which explains some of the liabilities of bioavailability information in greater technical detail. Bioavailability studies must be viewed as only one segment of the total product performance pattern. A bioavailability evaluation is a single study of one product lot. To the patient, clinical efficacy studies, quality assurance, stability. development and packaging programs must each function to achieve a quality drug product. Recent actions by the F.D.A. suggest that greater regulatory awareness and emphasis will be placed on these latter product programs. Enclosed are interoffice memoranda of the Abbott Laboratories concerning bioavailability studies conducted by the Upjohn Company. I should be very grateful if your staff would analyze this material with the possibility that it may be relevant to other studies conducted in this field. Thank you for your letter of March 3, 1975, requesting our comments on These memoranda make several valid points, and, in particular, they point out that comparing the bioavailability of drugs which are not generic equivalents may not be appropriate. Such drugs should not necessarily be expected to be comparable under all conditions of use, although when used as labeled they should be expected to provide comparable effectiveness. In It is important to note that the Upjohn studies referred to in the Abbott memoranda compared erythromycin base with erythromycin stearate. While both products contained the same active chemical moiety (erythromycin), they were not generic equivalents, i.e., not chemically identical. this instance the chemical variation introduced differences in the biopharmaceutic properties of the products. Specifically, as is noted, the oral erythromycin base as compared with the erythromycin stearate provides higher erythromycin serum levels when administered in the presence of food. The labeling of Abbott Laboratories' erythromycin stearate recognizes the effect of food on their product by stating, "Optimum blood levels are obtained when doses are given on an empty stomach." Interestingly, Abbott's interoffice correspondence includes a study comparing their erythromycin base with Upjohn's enteric coated erythromycin base. This too results in a study comparing two nonequivalent products due to the fact the enteric control product has been specifically formulated to prevent absorption of the active drug ingredient until it passes the stomach, whereas the nonenteric coated Abbott product begins to be absorbed earlier, while still in the stomach. |