PROCEEDINGS OF THE B.P.S., 3rd-5th JANUARY, 1979 425P
References KESSEL, D., HALL, T.C. & ROSENTHAL, D. (1969). Uptake and phosphorylation of cytosine arabinoside by normal and leukaemic blood cells in vitro. Cancer Res., 29, 459-463.
SMYTH, J.F., ROBINS, A.B. & LEESE, L.L. (1976). The metabolism of cytosine arabinoside as a predictive test for clinical response to the drug in acute myeloid leukaemia. Eur. J. Cancer, 12, 567-575.
Comparison of plasma theophylline concentrations achieved with a microcrystalline formulation and a sustained release preparation of theophylline
The mean plasma theophylline concentrations obtained with the two treatments are shown in Table 1. With MT, trough theophylline concentrations on days 3, 4 and 5 did not differ significantly from those obtained on day 2: mean plasma theophylline concentrations at 2 h rose significantly from day 1 to day 2, but subsequently no further significant increase occurred. With SRT, trough theophylline concentrations rose significantly from day 2 to day 3 but not from day 3 onwards. Plasma theophylline concentrations 4.5 h after SRT increased significantly from day 1 to day 2 but not thereafter. Comparing theophylline concentrations produced by MT with those from SRT, trough values were significantly higher with SRT on days 3 and 4 and the levels at 4.5 h after SRT were significantly higher than those measured 2 h after MT on days 3, 4 and 5. These results would indicate that the SRT preparation 375 mg 12 hourly produces plasma theophylline concentrations comparable to those resulting from an equivalent dose of MT, 187.5 mg every 6 h: in fact, over the last 3 days of the study, mean theophylline concentrations ranged between 11.2 and 15.5 gg/ml at measured trough and peak times with SRT, and were significantly higher on all occasions except one than the equivalent concentrations produced by MT. The SRT tablet would, therefore, appear to be an adequate sustained-release theophylline preparation, which produces therapeutic mean plasma concentrations with doses of 750 mg daily and achieves steady-state concentrations within 3 days of commencing treatment in normal subjects.
C.J. RUSSELL*, R.K. ELWOOD, C. KINNEY & D.G. McDEVITT Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Northern Ireland
It is generally accepted that plasma theophylline concentrations in the range 10-20 gig/ml are desirable for significant bronchodilator effects. Therefore, dosage regimens of theophylline compounds should be evaluated in these terms. We describe comparative studies between a microcrystalline formulation of theophylline (Nuelin, Riker Laboratories) (MT) and a new sustained release theophylline tablet (U4e, Riker Laboratories) (SRT) in normal volunteers. Fourteen normal volunteers, 11 males and 3 females, aged 20-35 years were studied. Each subject received MT 187.5 mg every 6 h SRT 375 mg every 12 h; thus the total daily dose for both was 750 mg. Both treatments were given for 5 days with at least 1 week separating them and the order of treatments was randomized. Blood samples were taken for estimation of plasma theophylline concentrations by high pressure liquid chromotography after the first dose on days 1 and 5 at 0.5, 1, 2, 3, 4.5 and 6 h with MT and at 0.5, 1, 2, 3, 4.5, 6, 9 and 12 h with SRT. On days 2, 3 and 4, blood samples were obtained before and 2 h after the morning dose (09.00 h) of MT and before and 4.5 h after the morning dose (09.00 h) of SRT.
We acknowledge help from Riker Laboratories both in the provision of the tablets in this study and financial assistance.
Table I Mean plasma theophylline concentrations (+ s.d.) before and 2 h after morning dose of MT 187.5 mg 6 hourly and before and 4.5 h after morning dose of SRT 375 mg 12 hourly for 5 days Plasma theophylline concentrations 4tglml) Day 4 Day 3 Day 2
Treatment Day 1 0
MT
P.
0
P*
0
8.6 8.2 11.8 +3.5 +3.4 ±3.1 0 SRT 11.2 5.5 13.1 9.5 +4.6 +2.0 +3.7 +5.3 (375 mg) P* 2 h with MT and 4.5 h with SRT after morning dose
(187.5 mg)
=
28
0
5.6
±1.8
P.
12.5 +4.8 15.5 +7.2
0
Day 5 P.
0
8.8
7.9 +3.8
11.5 ±4.2
+3.6
10.6 ±5.8
14.4 +6.2
11.3 +6.4
P.
12.5 +4.7 15.5 +6.4
References KESSEL, D., HALL, T.C. & ROSENTHAL, D. (1969). Uptake and phosphorylation of cytosine arabinoside by normal and leukaemic blood cells in vitro. Cancer Res., 29, 459-463.
SMYTH, J.F., ROBINS, A.B. & LEESE, L.L. (1976). The metabolism of cytosine arabinoside as a predictive test for clinical response to the drug in acute myeloid leukaemia. Eur. J. Cancer, 12, 567-575.
Comparison of plasma theophylline concentrations achieved with a microcrystalline formulation and a sustained release preparation of theophylline
The mean plasma theophylline concentrations obtained with the two treatments are shown in Table 1. With MT, trough theophylline concentrations on days 3, 4 and 5 did not differ significantly from those obtained on day 2: mean plasma theophylline concentrations at 2 h rose significantly from day 1 to day 2, but subsequently no further significant increase occurred. With SRT, trough theophylline concentrations rose significantly from day 2 to day 3 but not from day 3 onwards. Plasma theophylline concentrations 4.5 h after SRT increased significantly from day 1 to day 2 but not thereafter. Comparing theophylline concentrations produced by MT with those from SRT, trough values were significantly higher with SRT on days 3 and 4 and the levels at 4.5 h after SRT were significantly higher than those measured 2 h after MT on days 3, 4 and 5. These results would indicate that the SRT preparation 375 mg 12 hourly produces plasma theophylline concentrations comparable to those resulting from an equivalent dose of MT, 187.5 mg every 6 h: in fact, over the last 3 days of the study, mean theophylline concentrations ranged between 11.2 and 15.5 gg/ml at measured trough and peak times with SRT, and were significantly higher on all occasions except one than the equivalent concentrations produced by MT. The SRT tablet would, therefore, appear to be an adequate sustained-release theophylline preparation, which produces therapeutic mean plasma concentrations with doses of 750 mg daily and achieves steady-state concentrations within 3 days of commencing treatment in normal subjects.
C.J. RUSSELL*, R.K. ELWOOD, C. KINNEY & D.G. McDEVITT Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Northern Ireland
It is generally accepted that plasma theophylline concentrations in the range 10-20 gig/ml are desirable for significant bronchodilator effects. Therefore, dosage regimens of theophylline compounds should be evaluated in these terms. We describe comparative studies between a microcrystalline formulation of theophylline (Nuelin, Riker Laboratories) (MT) and a new sustained release theophylline tablet (U4e, Riker Laboratories) (SRT) in normal volunteers. Fourteen normal volunteers, 11 males and 3 females, aged 20-35 years were studied. Each subject received MT 187.5 mg every 6 h SRT 375 mg every 12 h; thus the total daily dose for both was 750 mg. Both treatments were given for 5 days with at least 1 week separating them and the order of treatments was randomized. Blood samples were taken for estimation of plasma theophylline concentrations by high pressure liquid chromotography after the first dose on days 1 and 5 at 0.5, 1, 2, 3, 4.5 and 6 h with MT and at 0.5, 1, 2, 3, 4.5, 6, 9 and 12 h with SRT. On days 2, 3 and 4, blood samples were obtained before and 2 h after the morning dose (09.00 h) of MT and before and 4.5 h after the morning dose (09.00 h) of SRT.
We acknowledge help from Riker Laboratories both in the provision of the tablets in this study and financial assistance.
Table I Mean plasma theophylline concentrations (+ s.d.) before and 2 h after morning dose of MT 187.5 mg 6 hourly and before and 4.5 h after morning dose of SRT 375 mg 12 hourly for 5 days Plasma theophylline concentrations 4tglml) Day 4 Day 3 Day 2
Treatment Day 1 0
MT
P.
0
P*
0
8.6 8.2 11.8 +3.5 +3.4 ±3.1 0 SRT 11.2 5.5 13.1 9.5 +4.6 +2.0 +3.7 +5.3 (375 mg) P* 2 h with MT and 4.5 h with SRT after morning dose
(187.5 mg)
=
28
0
5.6
±1.8
P.
12.5 +4.8 15.5 +7.2
0
Day 5 P.
0
8.8
7.9 +3.8
11.5 ±4.2
+3.6
10.6 ±5.8
14.4 +6.2
11.3 +6.4
P.
12.5 +4.7 15.5 +6.4
