Correspondence

Variation

in theophylline

clearance

rate

To the Editor:

Conclusions in the recent publication of Leung, Kalisker, and Bell’ are somewhat at variance with data presented by Ginchansky and Weinberge? at the American Academy of Allergy meeting in San Juan in March, 1976. 1 feel that the JOURNAL readers should be aware that these two studies began as a collaborative project designed while 1 was at the University of Colorado Medical Center in the Division of Clinical Pharmacology. When the data from our two institutions were compared, however, there were sufficient discrepancies in the manner in which the studies were conducted that it was agreed to report these sets of data separately Over a period of 4.2 t 1.9 mo (mean 2 SD), 16 of 23 patients initially examined at the National Jewish Hospital and Research Center underwent repeat determinations of clearance in a manner similar to that described by Leung, Kalisker, and Bell. The initial mean clearance for these patients was 1.32 +- 0.43 ml/kg/min and subsequently averaged 1.31 & 0.41 ml/kg/min, with changes in clearance among the individual patients ranging from -26 to +23%. No correlation of changes in clearance was observed with a variet:y of changes in routine antiasthmatic medications. Thus, we concluded that clinically important changes in clearance were not frequent over this time interval. This subsequently appeared to be confirmed in a report by Wyatt, Weinberger, and Hendeles,3 who described relative stability of weight-adjusted doses among 91 children over an average 8..mo period (range, S- 14 mo). Explanations for the differences in our data may be technical ,and/or related to patient selection. Since the determination of clearance was dependent upon precise data related to both serum concentration and the infusion rate of theophylline, we used a self-regulating pump (IVAC 500) which can assure a constant rate of delivery even in the face of varying positions of the patient that result in varying degrees of back pressure in the intravenous system. We had previously experienced difficulties with non-self-regulating systems which would deliver a constant flow over the 24-hr period when not connected to a patient but were less dependable under the actual test circumstances. The Harvard pump used by Leung, Kalisker, and Bell was not selfregulating, which is of some concern to me with relation to their data. Additionally, the patient selection for repeat clearance determination was different at the two institutions. Leung and co-workers stated that the patients were re-examined because of poor control. The repeat clearance, therefore, may have been performed at times when these patients were acutely symptomatic. In the study of Gin-

chansky and Weinberger, however, all re-examinations were elective with the patients in a stable clinical status. The only patients not re-examined were those discharged within too brief a period of time, and 70% of patients were thereby examined for clearance over time compared with 40% of Dr. Leung’s patients. The very fact that Dr. Leung found a statistically significant difference in the mean clearances performed at the two times suggests a systematic effect on clearance by some factor(s). Even if significant intrapatient variability of theophylline clearance does occur, an adequate sample of patient clearances performed under similar conditions should not normally result in progressive increases in the mean clearance of the group. Over longer periods, some overall decrease in group clearances might be expected because of age-related effects on theophylline clearance from 9 to 16 yr of age.*, 3 We therefore feel that the conclusions of Ginchansky and Weinberge? and Wyatt, Weinberger, and Hendeles3 suggesting relative stability of theophylline clearance and weight-adjusted dosage for periods of 6 to 12 mo are warranted. We are in agreement, however, regarding the potential for a variety of factors possibly to affect theophylline clearance. Troleandomycin,l a macrolide antibiotic, has been shown to decrease theophylline clearance by 508, and the erythromycinsj may have similar though lesser effects. Thus, there is unquestionably a potential for drugs such as Dilantin (suggested by Leung and co-workers as the cause of increased clearance in one of their twelve patients) to affect theophylline metabolism. Unfortunately, conclusions cannot be drawn from one such patient. In point of fact, if that patient and one other (No. 8) are removed, their data differ little from ours. Additional factors that may affect theophylline clearance have been reviewed in detail, and some of these or other unknown factors*, 3 could conceivably have played a role in some of the patients of Leung and co-workers who were acutely ill and receiving intensive therapy at the time of the second clearance determination. Our data among ambulatory patients receiving chronic theophylline therapy suggested that serum theophylline concentrations should be repeated after approximately six months during periods of rapid growth (e.g., among infants, toddlers, and adolescents), but less frequent measurements at about one-year intervals appeared adequate for children during the middle years when growth was slower. Additional measurements might be warranted during periods of major alterations in the patient’s clinical status, particularly in the presence of suggestive repeated or prolonged symptoms of theophylline toxicity such as nausea, Vol. 60, No. 4, pp. 271-272

272 Correspondence vomiting, diarrhea, or headache. Under normal circumstances, however, dosage requirements among an ambulatory population of asthmatic children appear sufficiently stable so as not to pose important problems during longterm chronic theophylline therapy. Miles Weinberger, M.D. Associate Professor of Pediatrics and Pharmacology Director of the Pediatric Allergy and Pulmonary Division University of Iowa Iowa City, Iowa 52242 REFERENCES 1. Leung, P., Kalisker, A., and Bell, T. D.: Variation in theophylline clearance rate with time in chronic childhood asthma, J. ALLERGY CLIN. IMMUNOL. 59:440-444, 1977. 2. Ginchansky, E., and Weinberger, M.: Relationship of theophylline clearance to oral dosage, J. Pediatr. 91:655, 1971. 3. Wyatt, R., Weinberger, M., and Hendeles, L.: Oral theophylline dosage for the management of chronic asthma. Presented at the American Congress of Allergy, New York, March 28, 1977. 4. Weinberger, M. M., Hudgel, D., Spector, S., et al.: Inhibition of theophylline clearance by troleandomycin, J. ALLERGY CLIN. IMMUNOL. 59:228-231, 1977. 5. Cummins, L. H., Kozak, P. P., and Gilman, S. A.: Erythromytin’s effect on theophylline blood level, Pediatrics 59: 144-145, 1977.

Reply To the Editor: Dr. Weinberger’s letter emphasizes several areas of agreement as well as concern with our study and conclusions. His first concern centered on patient selection. This is, perhaps, the most important point we must address. Studies originating from the National Asthma Center obviously involve subjects with severe, poorly controlled asthma; otherwise, institutional care would not be justified. For this reason, we have clearly indicated in our abstract and in the section on materials and methods that the study was directed at severe, poorly controlled asthma.’ We feel that such a population is the most logical to select for study since optimization of theophylline therapy is much more necessary in this group than in milder asthmatics. The consequences of altered theophylline clearance are much more likely to be of significance in this group as well. In the clinical situation, faced with poorly controlled asthma, we feel measurement of serum theophylline levels, rather than assumption that the kinetics have remained stable, is the wiser course of action. We should point out, however, that

J. ALLERGY

CLIN. IMMUNOL. OCTOBER 1977

our data were not obtained during acute status asthmaticus, but instead were obtained under more stable conditions, similar to the outpatient situation when asthma continues in the face of maximum oral and inhaled therapy. Another of Dr. Weinberger’s concerns, the accuracy of the Harvard infusion pump, seems more theoretical than actual. We are unaware of published data suggesting that the IVAC 500 is significantly superior or more reliable. Reputable investigators in the pharmacokinetic field continue to utilize the Harvard infusion pump.2* 3 Further, we reported that the variation in volume delivered upon calibration of this system between experiments was only l%, much too small a variation to account for the magnitude of changes of theophylline clearance observed. How large are the variations Dr. Weinberger observed when he “previously experienced difficulties with nonself-regulating systems. . .” ? Did this experience encompass the Harvard pump? Dr. Weinberger suggests that had we removed two subjects (No. 8 and No. 25) from our series, our results would have been in concordance with his. This is true, but we feel this would have unjustly biased our data and conclusions. Incidentally, we were pleased to see our findings confirmed in a recent publication from Taussig’s group4 where a mean intrapatient variability of theophylline clearance rate over a period of 3 to 9 months was 52%, nearly twice that of our group. Their range of variation was also large: -57% to 142%. Perhaps future studies might strive to select a spectrum representing all degrees of asthma severity, more accurately depicting the universe of asthma. In retrospect, collaborative studies involving several asthma populations aren’t such a bad idea, are they? Patrick Leung, Albert Kalisker, Thomas Bell, The National Asthma Center, Denver,

M.D. Ph. D . M.D. Colo.

REFERENCES 1. Leung, P., Kalisker, A., and Bell, T.: Variation in theophylline clearance rate with time in chronic childhood asthma, J. ALLERGY CLIN. IMMUNOL. 59:440, 1977. 2. Shand, D., Komhauser, D., and Wilkinson., G.: Effects of route of administration and blood flow on hepatic drug elimination, J. Pharmacol. Exp. Ther. 195:424, 1975. 3. Ueda, C., Ballard, B., and Rowland, M.: Concentration-time effect in quinidine disposition kinetics in rhesus monkey, J. Pharmacol. Exp. Ther. 200:859, 1977. 4. Walson, P., Strunk, R., and Taussig, L.: Intrapatient variability in theophylline kinetics, J. Pediatr. 91:321, 1977.

Variation in theophylline clearance rate.

Correspondence Variation in theophylline clearance rate To the Editor: Conclusions in the recent publication of Leung, Kalisker, and Bell’ are s...
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