The Effect of Repeated Oral Doses of Lornoxicam Elimination in Normal Human Volunteers M.
1 Ravic,
Department 1
A.
1 Johnston,
P.
1 Turner,
F.
2 Takacs,
of Clinical Pharmacology, St. Bartholomew’s Pharma AG.
on
and D. E.
Hospital,
Antipyrine 2 Rosenow
London EC1A 7BE, UK and
Hafsland Nycomed 2
Treatment with lornoxicam 4 mg twice daily for 14 d did not produce any change in salivary antipyrine elimination in 11 of 12 healthy volunteers. Anomalous results in one subject are presented and discussed.
Introduction Lornoxicam tenoxicam) is
(previously
known
as
chlor-
recently introduced non-steroidal anti-inflammatory drug which presently is undergoing clinical investigation.~ Because it may be taken therapeutically for long periods it was desirable to investigate the possible effect of its chronic administration on hepatic drugmetabolizing enzymes, using antipyrine elimination as a measure of their activity. A preliminary report of this study was presented at a symposium on lornoxicam in May, 1990.2
Subjects
a
and methods
Twelve healthy subjects (six female) aged 20-34 years, weighing 54-82 kg, participated in the study after giving consent to the protocol which had been approved by the local ethics committee. Exclusion criteria included a history of indigestion, peptic ulcer, bronchial asthma and pregnancy. No abnormality of renal or liver function was found in a routine biochemical screen on the subjects before the study. Antipyrine elimination was measured 7 d before and 14 d after beginning treatment with lornoxicam 4 mg twice daily. Antipyrine tablets, 1200 mg, were given orally with 100 ml water at 09.00 h, and salivary collections were made at 3, 6, 9, 12, 15, 24, 30 and 36 h after dosing. Subjects were not allowed any ethanolic drinks for 24 h before and 48 h after antipyrine administration. On the first day of lornoxicam treatment, a single 4 mg tablet of lornoxicam was administered orally at 9.00 h with 100 ml water. Each subject had undergone an overnight fast which was
Correspondence
continued until 4 h after dosing. Blood samples were collected from an intravenous cannula before and at 0.25, 0.5, I , 2, 3, 4, 8 and 12 h after dosing. When the last blood samples were taken at 12 h, volunteers were given their second dose of 4 mg lornoxicam. They then continued to take lornoxicam twice daily for the next 14 d, at the same time schedule. At 9.00 h on day 14, subjects took 1200 mg antipyrine and 4 mg lornoxicam together. Salivary and blood samples were taken at the same times after dosing as before.
Analytical methods Antipyrine concentrations in the saliva samples were measured by gas chromatography.’ The assay sensitivity was 1 mg 1-’ ; intra-assay coefficient of variation < 5% and inter-assay coefficient of variation < 7%. Plasma concentrations of lornoxicam were assayed by reverse phase HPLC with UV detection.’ Coefficients of variation for control samples of 150, 75 and 15 [tg 1-’ were 14%, 13% and 27%, respectively. Preliminary studies had shown that antipyrine and lornoxicam did not interfere with the estimation of the other. Pharmacokinetic analyses were performed by the computer programme ’Stripe’.~4 Pharmacokinetic parameters before and after the lornoxicam treatment period were compared using Student’s paired t-test.
Results All and
subjects completed the study satisfactorily no adverse drug effects were reported.
to: M. Ravic
Downloaded from het.sagepub.com at MCMASTER UNIV LIBRARY on March 10, 2015
.
376
Table 1 Pharmacokinetic for 14 d
parameters (mean ± s.e.m.)
of
Lornoxicam Lornoxicam plasma concentrations on days 1 and 14 were used to estimate compliance with treatment regimes. The observed values showed that in all subjects except one, concentrations were within the expected range. In this one subject, lornoxicam concentrations was very high on day 14, reaching a peak of 1550 ~g 1-1, which was almost three times higher than the peak concentration achieved in any other subjects (521 u.g 1-’). His pretreatment concentrations were within the same range as the other subjects.
Antipyrine Pharmacokinetic data for antipyrine given before and after lornoxicam treatment in 11 subjects are in Table 1. No statistically significant effect of lornoxicam is seen on AUC clearance, elimination half-life or volume of distribution of antipyrine. The results of the subject who demonstrated anomalous results with lornoxicam are shown separately, as his pretreatment antipyrine salivary concentrations differed markedly from those in all other volunteers. His AUC was 92 mg 1-1 h-’, which compared with a range of -1 for the other subjects. His 240-444 mg 1-1 h post-treatment concentrations were similar to those in the other subjects. We were unable to explain these anomalous results in terms of compliance or of drug effect, but decided not to use them in the group calculations and to present them separately.
given
Discussion In 11 of the 12 subjects studied, lornoxicam did not influence significantly the AUC, clearance, elimination half-life or volume of distribution of antipyrine, the values of which were similar to those obtained in larger numbers of normal subjects 5.6 and in earlier studies in our department .7, The results in the other subject are
antipyrine given before
and after lornoxicam treatment
difficult to explain. His control, pretreatment lornoxicam plasma concentrations were within the same range as the other subjects and those that we have found elsewhere.’ The very high values found after 14 d treatment could be the result of accumulation due to reduced elimination or failure to comply with the protocol and, for example the ingestion of a high dosc of lornoxicam on day 13 or day 14. It is of interest that his 09.00 h sample on day 14 contained lornoxicam 1159.4 Rg 1-’ compared with a range of 18.4-240.8 ~g 1-’ in the other 11 subjects. This is consistent with the possibility that lornoxicam inhibited its own metabolism, and also that of antipyrine, in this subject. The results in the other subjects showed no evidence of delayed antipyrine excretion, however, but rather a non-significant trend towards increased elimination. Recent studies9 in human volunteers have suggested that a major metabolite of lornoxicam is 51-hydroxylornoxicam. It is of interest that our anomalous subject was subsequently found to be a poor hydroxylator of debrisoquine, and it may be, therefore, that he was also deficient in his capacity to hydroxylate lornoxicam. One other subject has been described in the literature’ who demonstrated unexpectedly high CmaX values, associated with a long elimination half-life, after 7 d treatment with lornoxicam 6 mg twice daily. He was subsequently found to be an extensive hydroxylator of debrisoquine and it is unlikely, therefore, that his slow elimination of lornoxicam was associated with the same form of defective hydroxylation. Our results suggest that lornoxicam in a dose of 4 mg twice daily over a 14-d period had generally no significant effect on antipyrine elimination. In particular, in the light of evidence of inhibition of warfarin clearance by lornoxicam,10 there was no evidence of inhibition of antipyrine clearance. The anomalous results in one subject, however, suggest that further studies are required on the routes of metabolism of lornoxicam, and on its pharmacokinetic
Downloaded from het.sagepub.com at MCMASTER UNIV LIBRARY on March 10, 2015
377
in larger numbers of subjects after single doses and prolonged treatment, with particular reference to hydroxylation capacities.
phenazone plasma half-lives in young healthy volunteers. European Journal of Clinical Pharmacology 1974; 7: 381-5.
properties
4 Johnston A & Wooland RC. STRIPE: an interactive computer programme for the analysis of drug pharmacokinetics. Journal of Pharmacological Methods 1983; 9: 193200.
Acknowledgements Q
We thank Dr R. 4ohn and his colleagues, Advisory Services (Clinical and General) Ltd, for their collabora-
tion.
References 1 Ankier SI, Brimelow AE, Crome P et al. Chlortenoxicam pharmacokinetics in young and elderly human volunteers. Postgraduate Medical Journal 1988; 64: 752-4. 2 Ravic M, Johnston A & Turner P. Clinical pharmacological studies of some possible interactions of lornoxicam with other drugs. Postgraduate Medical Journal 1990; 66 (Suppl. S30-4. 4): 3 Lindgren S, Collste P, Norlander B & Sjoquist F. Gas chromatographic assessment of the reproducibility of
5 Fraser HS, Mucklow JC, Murray S & Davies DS. Assessment of antipyrine kinetics by measurement of saliva. British Journal of Clinical Pharmacology 1976; 3: 321-5. 6 Stevenson IH. Factors influencing antipyrine eliminaiton. British Journal of Clinical Pharmacology 1977; 4: 261-5. 7 Hedges A, Warrington SJ, Turner P & Niebch G. Flupirtine maleate and antipyrine half-life. European Journal of Clinical Pharmacology 1987; 33: 437. 8 Johnston A, Warrington SJ, Turner P & Aurich R. The effect of repeated oral doses of azelastine hydrochloride on 9
10
antipyrine half-life in normal volunteers. Pharmacy and Pharmacology 1988; 40: 225. Hitzenberger G, Radhofer-Welte S, Takacs F
Journal &
of
Rosenow
D. Pharmacokinetics of lornoxicam in man. Postgraduate Medical Journal 1990; 66 (Suppl. 4): S22-6. Ravic M, Johnston A, Turner P & Ferber HP. A study of the interaction between lornoxicam and warfarin in healthy volunteers. Human and Experimental Toxicology 1990; 9, 413-14.
(Received
17 December 1990;
Downloaded from het.sagepub.com at MCMASTER UNIV LIBRARY on March 10, 2015
accepted
13
February 1991)
1 Ravic,
Department 1
A.
1 Johnston,
P.
1 Turner,
F.
2 Takacs,
of Clinical Pharmacology, St. Bartholomew’s Pharma AG.
on
and D. E.
Hospital,
Antipyrine 2 Rosenow
London EC1A 7BE, UK and
Hafsland Nycomed 2
Treatment with lornoxicam 4 mg twice daily for 14 d did not produce any change in salivary antipyrine elimination in 11 of 12 healthy volunteers. Anomalous results in one subject are presented and discussed.
Introduction Lornoxicam tenoxicam) is
(previously
known
as
chlor-
recently introduced non-steroidal anti-inflammatory drug which presently is undergoing clinical investigation.~ Because it may be taken therapeutically for long periods it was desirable to investigate the possible effect of its chronic administration on hepatic drugmetabolizing enzymes, using antipyrine elimination as a measure of their activity. A preliminary report of this study was presented at a symposium on lornoxicam in May, 1990.2
Subjects
a
and methods
Twelve healthy subjects (six female) aged 20-34 years, weighing 54-82 kg, participated in the study after giving consent to the protocol which had been approved by the local ethics committee. Exclusion criteria included a history of indigestion, peptic ulcer, bronchial asthma and pregnancy. No abnormality of renal or liver function was found in a routine biochemical screen on the subjects before the study. Antipyrine elimination was measured 7 d before and 14 d after beginning treatment with lornoxicam 4 mg twice daily. Antipyrine tablets, 1200 mg, were given orally with 100 ml water at 09.00 h, and salivary collections were made at 3, 6, 9, 12, 15, 24, 30 and 36 h after dosing. Subjects were not allowed any ethanolic drinks for 24 h before and 48 h after antipyrine administration. On the first day of lornoxicam treatment, a single 4 mg tablet of lornoxicam was administered orally at 9.00 h with 100 ml water. Each subject had undergone an overnight fast which was
Correspondence
continued until 4 h after dosing. Blood samples were collected from an intravenous cannula before and at 0.25, 0.5, I , 2, 3, 4, 8 and 12 h after dosing. When the last blood samples were taken at 12 h, volunteers were given their second dose of 4 mg lornoxicam. They then continued to take lornoxicam twice daily for the next 14 d, at the same time schedule. At 9.00 h on day 14, subjects took 1200 mg antipyrine and 4 mg lornoxicam together. Salivary and blood samples were taken at the same times after dosing as before.
Analytical methods Antipyrine concentrations in the saliva samples were measured by gas chromatography.’ The assay sensitivity was 1 mg 1-’ ; intra-assay coefficient of variation < 5% and inter-assay coefficient of variation < 7%. Plasma concentrations of lornoxicam were assayed by reverse phase HPLC with UV detection.’ Coefficients of variation for control samples of 150, 75 and 15 [tg 1-’ were 14%, 13% and 27%, respectively. Preliminary studies had shown that antipyrine and lornoxicam did not interfere with the estimation of the other. Pharmacokinetic analyses were performed by the computer programme ’Stripe’.~4 Pharmacokinetic parameters before and after the lornoxicam treatment period were compared using Student’s paired t-test.
Results All and
subjects completed the study satisfactorily no adverse drug effects were reported.
to: M. Ravic
Downloaded from het.sagepub.com at MCMASTER UNIV LIBRARY on March 10, 2015
.
376
Table 1 Pharmacokinetic for 14 d
parameters (mean ± s.e.m.)
of
Lornoxicam Lornoxicam plasma concentrations on days 1 and 14 were used to estimate compliance with treatment regimes. The observed values showed that in all subjects except one, concentrations were within the expected range. In this one subject, lornoxicam concentrations was very high on day 14, reaching a peak of 1550 ~g 1-1, which was almost three times higher than the peak concentration achieved in any other subjects (521 u.g 1-’). His pretreatment concentrations were within the same range as the other subjects.
Antipyrine Pharmacokinetic data for antipyrine given before and after lornoxicam treatment in 11 subjects are in Table 1. No statistically significant effect of lornoxicam is seen on AUC clearance, elimination half-life or volume of distribution of antipyrine. The results of the subject who demonstrated anomalous results with lornoxicam are shown separately, as his pretreatment antipyrine salivary concentrations differed markedly from those in all other volunteers. His AUC was 92 mg 1-1 h-’, which compared with a range of -1 for the other subjects. His 240-444 mg 1-1 h post-treatment concentrations were similar to those in the other subjects. We were unable to explain these anomalous results in terms of compliance or of drug effect, but decided not to use them in the group calculations and to present them separately.
given
Discussion In 11 of the 12 subjects studied, lornoxicam did not influence significantly the AUC, clearance, elimination half-life or volume of distribution of antipyrine, the values of which were similar to those obtained in larger numbers of normal subjects 5.6 and in earlier studies in our department .7, The results in the other subject are
antipyrine given before
and after lornoxicam treatment
difficult to explain. His control, pretreatment lornoxicam plasma concentrations were within the same range as the other subjects and those that we have found elsewhere.’ The very high values found after 14 d treatment could be the result of accumulation due to reduced elimination or failure to comply with the protocol and, for example the ingestion of a high dosc of lornoxicam on day 13 or day 14. It is of interest that his 09.00 h sample on day 14 contained lornoxicam 1159.4 Rg 1-’ compared with a range of 18.4-240.8 ~g 1-’ in the other 11 subjects. This is consistent with the possibility that lornoxicam inhibited its own metabolism, and also that of antipyrine, in this subject. The results in the other subjects showed no evidence of delayed antipyrine excretion, however, but rather a non-significant trend towards increased elimination. Recent studies9 in human volunteers have suggested that a major metabolite of lornoxicam is 51-hydroxylornoxicam. It is of interest that our anomalous subject was subsequently found to be a poor hydroxylator of debrisoquine, and it may be, therefore, that he was also deficient in his capacity to hydroxylate lornoxicam. One other subject has been described in the literature’ who demonstrated unexpectedly high CmaX values, associated with a long elimination half-life, after 7 d treatment with lornoxicam 6 mg twice daily. He was subsequently found to be an extensive hydroxylator of debrisoquine and it is unlikely, therefore, that his slow elimination of lornoxicam was associated with the same form of defective hydroxylation. Our results suggest that lornoxicam in a dose of 4 mg twice daily over a 14-d period had generally no significant effect on antipyrine elimination. In particular, in the light of evidence of inhibition of warfarin clearance by lornoxicam,10 there was no evidence of inhibition of antipyrine clearance. The anomalous results in one subject, however, suggest that further studies are required on the routes of metabolism of lornoxicam, and on its pharmacokinetic
Downloaded from het.sagepub.com at MCMASTER UNIV LIBRARY on March 10, 2015
377
in larger numbers of subjects after single doses and prolonged treatment, with particular reference to hydroxylation capacities.
phenazone plasma half-lives in young healthy volunteers. European Journal of Clinical Pharmacology 1974; 7: 381-5.
properties
4 Johnston A & Wooland RC. STRIPE: an interactive computer programme for the analysis of drug pharmacokinetics. Journal of Pharmacological Methods 1983; 9: 193200.
Acknowledgements Q
We thank Dr R. 4ohn and his colleagues, Advisory Services (Clinical and General) Ltd, for their collabora-
tion.
References 1 Ankier SI, Brimelow AE, Crome P et al. Chlortenoxicam pharmacokinetics in young and elderly human volunteers. Postgraduate Medical Journal 1988; 64: 752-4. 2 Ravic M, Johnston A & Turner P. Clinical pharmacological studies of some possible interactions of lornoxicam with other drugs. Postgraduate Medical Journal 1990; 66 (Suppl. S30-4. 4): 3 Lindgren S, Collste P, Norlander B & Sjoquist F. Gas chromatographic assessment of the reproducibility of
5 Fraser HS, Mucklow JC, Murray S & Davies DS. Assessment of antipyrine kinetics by measurement of saliva. British Journal of Clinical Pharmacology 1976; 3: 321-5. 6 Stevenson IH. Factors influencing antipyrine eliminaiton. British Journal of Clinical Pharmacology 1977; 4: 261-5. 7 Hedges A, Warrington SJ, Turner P & Niebch G. Flupirtine maleate and antipyrine half-life. European Journal of Clinical Pharmacology 1987; 33: 437. 8 Johnston A, Warrington SJ, Turner P & Aurich R. The effect of repeated oral doses of azelastine hydrochloride on 9
10
antipyrine half-life in normal volunteers. Pharmacy and Pharmacology 1988; 40: 225. Hitzenberger G, Radhofer-Welte S, Takacs F
Journal &
of
Rosenow
D. Pharmacokinetics of lornoxicam in man. Postgraduate Medical Journal 1990; 66 (Suppl. 4): S22-6. Ravic M, Johnston A, Turner P & Ferber HP. A study of the interaction between lornoxicam and warfarin in healthy volunteers. Human and Experimental Toxicology 1990; 9, 413-14.
(Received
17 December 1990;
Downloaded from het.sagepub.com at MCMASTER UNIV LIBRARY on March 10, 2015
accepted
13
February 1991)
