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1 A short term comparison of two sustained release (SR) theophylline (T) preparations in asthmatic children
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A SHORT TERM COMPARISON OF TWO SUSTAINED RELEASE (SR) THEOPHYLLINE (T) PREPARATIONS IN ASTHMATIC CHILDREN. G. Rachilefsky, M.D., A. Rohr, M.D., J. Wo, R.N., V. Gracey, R.N., R. Katz, M.D., S. Spector, M.D., M. Lefkowitz, M.S., S. Siegel, M.D., Los Angeles, CA. In a 4-week study, 20 children with chronic asthma were treated in a randomized doubleblind, cross-over manner with Theo-dur@(TD) and Uniphyl@(U) to compare their serum drug concentrations and clinical efficacy. Twelve hour doses (to achieve T levels between lo-20 ug/ml) of each drug were given for 2 weeks. Diaries of asthma symptoms and peak flows were kept daily. T levels were checked at 6 to 10 hrs, 4 days after starting each drug. After 14 days of each treatment, children returned for T levels and PFTs at 0, 1, 2, 4, 6, 8, 10 and 12 hours; that day's T was administered 30-45 minutes after the child's usual breakfast. To date, data from the first 15 children have been analyzed. Mean TD levels peaked at 6 hrs (14.8 ug/ml) while mean U peaked at 4 hrs (13.0 ug/ml) (p=N.S.) Difference between mean high and low levels with U was less than with T; U demonstrated a smoother curve, with less variance of levels over time. Both drugs were equally effective in clinically controlling asthma over the 2 weeks of treatment. UniphylQD and Theo-dur@ are equally effective though U has the advantage in children of: 1) less difference between peak and trough levels and 2) greater latitude in adjusting dose into therapeutic window.
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SUSTAINED RELEASE THEOPHYLLINE (SRT): ABSORPTION IN YOUNG CHiLDREN. J.R. Haltom, M.D. and S.J. Szefler, M.D., Denver, Colorado Clinicians have recently been notified that SRT preparations are not recommended for children less than 6 yrs of age. Since it is important to identify adequate preparations for this age group, we conducted detailed studies with 2 separate SRTs. Eight asthmatic children, ages Z-6 yrs, were selected. After an IV aminophylline study to obtain essential pharmacokinetic parameters, each child received Slo-Bid Gyrocaps (S-B, Rarer) q 12 hrs and Slo-Phyllin Gyrocaps (S-P, Rarer) q 8 hrs for 7 days each. On day 7 of each study period, serum theophylline concentrations (STC) were obtained every 2 hrs for 24 hrs and absorption over time calculated. Comparing S-B and S-P, neither the mean oral dose in mg/kg/d (25 * 1.4 S.E.M. vs. 24 * 1.5) nor the mean STC over 24 hrs (Il.8 significantly. The
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* 9.9 vs. 12.1 * 1.2 ug/ml) varied absorption patterns showed a
marked difference between the two preparations. S-B was essentially 100.96bioavailable at both the morning (97 * 906) and evening (99 f IO?&) doses and showed a consistent rise in STCs to a peak 4-6 hrs after each dose. S-P showed no consistent peak-trough effect and had considerable dose-to-dose variation in J bioavailability
as follows:
(a) 0800 hrs - 102 r 14; (b) 1600 hrs -
77 +- 15; and (c) 2400 hrs - 141 * 13. These differences indicate
delayed
and then overlapping
absorption
with
the 1600 and 2400 hr doses, respectively. Although both drugs are essentially 100% bioavailable over a 24-hr period, their absorption characteristics can vary considerably. S-B appears to be a satisfactory
SRT for twice
daily
administration
2-6 yrs of age, but the potential variation
in children
for intrapatient
in STCs must be recognized.
105
DETERMINATION OF IN VIVO MEAN ABSORPTION AND DISSOLUTION TIMES OF SUSTAINED-RELEASE THEOPHYLLINE PREPARATIONS. C.L. Saccar, Pharm.D. Ph.D. and H.C. Mansmann, Jr., M.L. Rocci, Jr., Pa. M.D., Phila.! The absorption characteristics of two sustained-release theophylline (SRT) products, Aerolate@ (AE) and Theo-DurB (TH) were compared to an immediate-release standard (IRS) using noncompartmental pharmacokinetics in contrast to conventional compartmental means. Fifteen males, 23-43 years, rececbed single doses of AE (520 ms) , TH (500 mg) and IRS (400 mg) in a randomized Blood samples were collected crossover design. for 48 hours for serum theophylline determinaMoment analysis was used to compute the tions. mean residence time (MRT), relative dispersion time (MAT) and mean dis(RD), mean absorption The mean + SD values are solution time (MDT). as follows: MAT*(hr) MDT*(hr) RD*(hr2) PROD MRT*(hr) IRS 11.1+2.OA 0.94tO.058 0.6+0.6A -------AE 16.0+1.9B 0.75+0.06B 5.6?1.7~ 5.021.7A TH 16.8+2.3B 0.71+0.05C 6.4+1.6B 5.7+1.5A *Means with different letters are significantly different (~~0.05). There were no significant differences in MRT, MAT and MDT between the two SRT products. While the RD for AE and TH were statistically difthese differences do not appear to be ferent, AE and TH appear to be clinically significant. comparable in their absorption characteristics. Noncompartmental pharmacokinetics may be a useful tool in examining the absorption characteristics the degree of of SRT products, thus, delineating product variability.
THE EFFECT OF FOOD ON ONCE DAILY THEO-DUR@ IN ASTHMATIC SUBJECTS. S.L. Spector, M. D., Rohr, M.D., G.S. Rachelefsky, M.D., A.S. R.M. Katz, M.D., S.C. Siegel, M.D., Julie Wo, R.N,, Vickie Gracey, R.N. Los Angeles, CA. Ten asthmatics on twice daily Theo-dur@, 900 mg or less were given their total daily dose with and without a high fat breakfast. Theophylline blood levels were drawn before and 1, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours In 3 subjects the study days post dosing. were repeated 4-5 months later to determine individual serum theophylline level consistencies. There was a significant delay in absorption when food was given simultaneously with Theo-dur@ at hours 2, 3, 4, 5 and 6. Some individuals showed a "tight" pattern and others, greater swings in theophylline blood levels exceeding 100% peak to trough fluctuations. Two patients studied twice had similar patterns in theophylline kinetics, but with differences in theophylline baseline despite the same regimen. A third asymptomatic patient had a baseline theophylline >2X that seen in a previous study and developed theophylline toxicity. Thus, a high fat breakfast in the same patient delays the absorption of once daily Theo-dur@ given in Although patients doses of 900 mg or less. may show similar patterns of theophylline kinetics, baseline theophylline values may differ from day to day. Pre-dose theophylline values should be known on the day the total 24-hour dose is given as a safety precaution.
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A SHORT TERM COMPARISON OF TWO SUSTAINED RELEASE (SR) THEOPHYLLINE (T) PREPARATIONS IN ASTHMATIC CHILDREN. G. Rachilefsky, M.D., A. Rohr, M.D., J. Wo, R.N., V. Gracey, R.N., R. Katz, M.D., S. Spector, M.D., M. Lefkowitz, M.S., S. Siegel, M.D., Los Angeles, CA. In a 4-week study, 20 children with chronic asthma were treated in a randomized doubleblind, cross-over manner with Theo-dur@(TD) and Uniphyl@(U) to compare their serum drug concentrations and clinical efficacy. Twelve hour doses (to achieve T levels between lo-20 ug/ml) of each drug were given for 2 weeks. Diaries of asthma symptoms and peak flows were kept daily. T levels were checked at 6 to 10 hrs, 4 days after starting each drug. After 14 days of each treatment, children returned for T levels and PFTs at 0, 1, 2, 4, 6, 8, 10 and 12 hours; that day's T was administered 30-45 minutes after the child's usual breakfast. To date, data from the first 15 children have been analyzed. Mean TD levels peaked at 6 hrs (14.8 ug/ml) while mean U peaked at 4 hrs (13.0 ug/ml) (p=N.S.) Difference between mean high and low levels with U was less than with T; U demonstrated a smoother curve, with less variance of levels over time. Both drugs were equally effective in clinically controlling asthma over the 2 weeks of treatment. UniphylQD and Theo-dur@ are equally effective though U has the advantage in children of: 1) less difference between peak and trough levels and 2) greater latitude in adjusting dose into therapeutic window.
3
SUSTAINED RELEASE THEOPHYLLINE (SRT): ABSORPTION IN YOUNG CHiLDREN. J.R. Haltom, M.D. and S.J. Szefler, M.D., Denver, Colorado Clinicians have recently been notified that SRT preparations are not recommended for children less than 6 yrs of age. Since it is important to identify adequate preparations for this age group, we conducted detailed studies with 2 separate SRTs. Eight asthmatic children, ages Z-6 yrs, were selected. After an IV aminophylline study to obtain essential pharmacokinetic parameters, each child received Slo-Bid Gyrocaps (S-B, Rarer) q 12 hrs and Slo-Phyllin Gyrocaps (S-P, Rarer) q 8 hrs for 7 days each. On day 7 of each study period, serum theophylline concentrations (STC) were obtained every 2 hrs for 24 hrs and absorption over time calculated. Comparing S-B and S-P, neither the mean oral dose in mg/kg/d (25 * 1.4 S.E.M. vs. 24 * 1.5) nor the mean STC over 24 hrs (Il.8 significantly. The
4
* 9.9 vs. 12.1 * 1.2 ug/ml) varied absorption patterns showed a
marked difference between the two preparations. S-B was essentially 100.96bioavailable at both the morning (97 * 906) and evening (99 f IO?&) doses and showed a consistent rise in STCs to a peak 4-6 hrs after each dose. S-P showed no consistent peak-trough effect and had considerable dose-to-dose variation in J bioavailability
as follows:
(a) 0800 hrs - 102 r 14; (b) 1600 hrs -
77 +- 15; and (c) 2400 hrs - 141 * 13. These differences indicate
delayed
and then overlapping
absorption
with
the 1600 and 2400 hr doses, respectively. Although both drugs are essentially 100% bioavailable over a 24-hr period, their absorption characteristics can vary considerably. S-B appears to be a satisfactory
SRT for twice
daily
administration
2-6 yrs of age, but the potential variation
in children
for intrapatient
in STCs must be recognized.
105
DETERMINATION OF IN VIVO MEAN ABSORPTION AND DISSOLUTION TIMES OF SUSTAINED-RELEASE THEOPHYLLINE PREPARATIONS. C.L. Saccar, Pharm.D. Ph.D. and H.C. Mansmann, Jr., M.L. Rocci, Jr., Pa. M.D., Phila.! The absorption characteristics of two sustained-release theophylline (SRT) products, Aerolate@ (AE) and Theo-DurB (TH) were compared to an immediate-release standard (IRS) using noncompartmental pharmacokinetics in contrast to conventional compartmental means. Fifteen males, 23-43 years, rececbed single doses of AE (520 ms) , TH (500 mg) and IRS (400 mg) in a randomized Blood samples were collected crossover design. for 48 hours for serum theophylline determinaMoment analysis was used to compute the tions. mean residence time (MRT), relative dispersion time (MAT) and mean dis(RD), mean absorption The mean + SD values are solution time (MDT). as follows: MAT*(hr) MDT*(hr) RD*(hr2) PROD MRT*(hr) IRS 11.1+2.OA 0.94tO.058 0.6+0.6A -------AE 16.0+1.9B 0.75+0.06B 5.6?1.7~ 5.021.7A TH 16.8+2.3B 0.71+0.05C 6.4+1.6B 5.7+1.5A *Means with different letters are significantly different (~~0.05). There were no significant differences in MRT, MAT and MDT between the two SRT products. While the RD for AE and TH were statistically difthese differences do not appear to be ferent, AE and TH appear to be clinically significant. comparable in their absorption characteristics. Noncompartmental pharmacokinetics may be a useful tool in examining the absorption characteristics the degree of of SRT products, thus, delineating product variability.
THE EFFECT OF FOOD ON ONCE DAILY THEO-DUR@ IN ASTHMATIC SUBJECTS. S.L. Spector, M. D., Rohr, M.D., G.S. Rachelefsky, M.D., A.S. R.M. Katz, M.D., S.C. Siegel, M.D., Julie Wo, R.N,, Vickie Gracey, R.N. Los Angeles, CA. Ten asthmatics on twice daily Theo-dur@, 900 mg or less were given their total daily dose with and without a high fat breakfast. Theophylline blood levels were drawn before and 1, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours In 3 subjects the study days post dosing. were repeated 4-5 months later to determine individual serum theophylline level consistencies. There was a significant delay in absorption when food was given simultaneously with Theo-dur@ at hours 2, 3, 4, 5 and 6. Some individuals showed a "tight" pattern and others, greater swings in theophylline blood levels exceeding 100% peak to trough fluctuations. Two patients studied twice had similar patterns in theophylline kinetics, but with differences in theophylline baseline despite the same regimen. A third asymptomatic patient had a baseline theophylline >2X that seen in a previous study and developed theophylline toxicity. Thus, a high fat breakfast in the same patient delays the absorption of once daily Theo-dur@ given in Although patients doses of 900 mg or less. may show similar patterns of theophylline kinetics, baseline theophylline values may differ from day to day. Pre-dose theophylline values should be known on the day the total 24-hour dose is given as a safety precaution.