The pharmacokinetics of nedocromil sodium, a new drug for the treatment of reversible obstructive airways disease, in.

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1 Br. J. clin. Pharmac. (1987), 24, The pharmacokinetics of nedocromil sodium, a new drug for the treatment of reversible obstructive airways disease, in human volunteers and patients with reversible obstructive airways disease M. G. NEALE, K. BROWN, R. A. FOULDS, S. LAL1, D. A. MORRIS & D. THOMAS Departments of Clinical Pharmacology and Drug Metabolism, Fisons plc, Pharmaceutical Division, Loughborough, Leicestershire, LE11 ORH and 'Chest Unit, Bury General Hospital, Bury, Lancashire 1 The plasma concentrations and urinary excretion of nedocromil sodium have been determined following single dose administration in six healthy volunteers dosed orally (1 mg kg- 1) and intravenously (0.2,ug kg- 1 for 30 min). Similar parameters were measured in six volunteers and twelve asthmatic patients dosed by inhalation (4 mg). Multiple dose kinetic measurements were also made. 2 The intravenous data demonstrated that nedocromil sodium is a high clearance drug (10.2 ± 1.3 ml min-' kg-'). The data were fitted by a two compartment model with very rapid elimination from the central compartment (klo = ± min-1;,b = min-'). 81% of the dose was excreted in the urine. 3 Oral absorption was low (2-3% of the dose) and contributed negligibly to the plasma profile after inhalation. 4 After inhalation of single doses of 4 mg in volunteers and patients plasma concentration rose rapidly, plateaued and then fell monoexponentially with a half-life of approximately 2 h. The data fitted a 'ffip-flop' model with two absorption components. The extent of absorption was up to 6% of the dose with less in patients. 5 After multiple dosing with 4 mg four times daily for 7 days in volunteers negligible accumulation was observed. The pattern was similar in patients treated with 4 mg four times daily after 1, 6 and 12 months. Keywords pharmacokinetics nedocromil sodium airways disease Introduction Nedocromil sodium is the disodium salt of a 1985; Shaw & Kay, 1985; Youngchaiyud & Lee, pyranoquinoline dicarboxylic acid which has been 1986) as well as being active in therapeutic trials developed as a new treatment (Tilade9, (Lal et al., 1984; Ruffin, 1986; Fairfax & Allbeson registered trade mark of Fisons plc) for reversible 1986). obstructive airways disease (Auty, 1986; Orr et A sensitive radioimmunoassay for nedocromil al., 1986). The drug is administered by inhalation sodium in plasma was developed (Gardner etal., using a metered dose aerosol and it has been 1987) and this has been used in the present investishown to protect against various bronchial chal- gations to measure plasma concentrations and lenges in asthmatic patients (Roberts & Thomson, urinary excretion of the drug in healthy volunteers Correspondence: Dr M. G. Neale, Department of Clinical Pharmacology, Fisons plc, Pharmaceutical Division, Loughborough, Leicestershire LE11 ORH 493

2 494 M. G. Neale et al. using the inhaled route of administration. Plasma concentrations resulting from both single inhaled doses of 4 mg and from multiple dosing of 4 mg four times daily for 7 days have been investigated. Since a large proportion of the dose of a drug administered by inhalation is deposited in the oro-pharyngeal region (Newman et al., 1981), the pharmacokinetics of nedocromil sodium given via the oral route have also been studied. Also in order to ascertain the fate of the compound once absorbed, the pharmacokinetics of the drug given intravenously have been investigated. The results of these studies are described in this paper. It is important to assess the pharmacokinetics of a new drug in patients, particularly where the organ of administration is the 'diseased organ' as in the case of inhalation treatment of reversible obstructive airways disease. The present study also included, therefore, an investigation of the pharmacokinetics of nedocromil sodium in asthmatic patients after a single dose by inhalation. As the patients involved were taking part in a 12 month open assessment trial (Lal et al., 1986) of the effectiveness of nedocromil sodium in the management of bronchial asthma the opportunity was taken to monitor the plasma concentrations after 1, 6 and 12 months of treatment. Interpretation of the pharmacokinetic results is not complicated by metabolism as separate studies in animals and man with 14C-labelled nedocromil sodium revealed no metabolism (Brown, unpublished data). Methods Overall design For the volunteer studies two groups of healthy subjects were involved. Initially seven subjects participated in a two-way crossover in which volunteers received a slow intravenous infusion or an oral dose of nedocromil sodium in random order on separate occasions 7 days apart. Plasma and urine concentrations of nedocromil sodium were measured after dosing. In a second, separate group of six subjects plasma and urine concentrations were similarly measured after a single dose of nedocromil sodium (4 mg) given by inhalation and then again, after a washout period of 7 days, on the first and last days of a 7 day multiple dosing period (4 mg four times a day). Both studies were approved by an independent Ethics Review Committee. The patient study was part of a 12 month open assessment trial (Lal et al., 1986) in which 44 asthmatic patients participated. Twelve of these patients were selected, on the basis of willingness to take part, to have detailed blood and urine samples collected after the first dose of nedocromil sodium. One month later, less detailed blood and urine samples were collected and then after 6 and 12 months blood samples alone were collected. All plasma and urine samples were analysed for nedocromil sodium. This study was approved by the hospital Ethics Committee and written informed consent was obtained from all the patients. Volunteer studies Subjects All subjects were healthy volunteers who had given fully informed written consent to take part. The first group consisted of seven subjects, three male and four female, with a range of ages from 22 to 54 years. Mean weights were 70 and 71 kg for the males and females respectively. The second group consisted of six subjects, three of each sex, with ages ranging from 28 to 44 years and with mean weights of 69 and 62 kg respectively. The subjects in the first group received both intravenous and oral doses while those in the second group received the single and multiple inhalation doses. Treatments Intravenous-the intravenous formulation consisted of a sterile solution of nedocromil sodium (25,ug ml-') in 0.9% sodium choride. Each subject received an infusion of 0.2,ug kg-1 min-' for a period of 30 min giving a total dose of 6,ug kg-'. One female subject did not receive the intravenous dose due to technical difficulties with cannulation Oral-the oral formulation consisted of a solution of nedocromil sodium in water. The dose was 1 mg kg-1 and all subjects received the dose in 100 ml of solution; the vessel containing the dose was rinsed with a further 50 ml of water which was taken by the subject. Inhalation-nedocromil sodium was administered from a pressurised aerosol formulation (Tilade ) similar to that used in clinical trials. Each actuation of the device delivered a nominal 2 mg dose and each dose consisted of two actuations (i.e. total dose was 4 mg). Dosing was carried out under close supervision, the subjects having familiarised themselves with the correct procedure by practice with dummy cans. Standard mouthpieces were used and a closed-mouth technique was employed. Subjects aimed to coordinate actuation of the aerosol with the beginning of a deep inspiration; the breath was held for 10 s after each actuation and consecutive breaths were used for dosing. The single doses were taken at h: the multiple doses of 2 x 2 mg four times daily were taken at 08.00, 13.00,

3 13.00, and 23.00h. On the final day only two doses were taken at and 13.00h. Procedure On all study days when blood samples were taken subjects reported to the laboratory having fasted overnight. After intravenous cannulae had been inserted and control samples of blood and urine collected, dosing was carried out as described above. Blood samples (5 ml) were taken from the indwelling venous cannula which was kept patent with heparin 10iu ml-1. The timing of blood and urine samples varied according to the route of administration and is described below. Intravenous dosing-blood samples were take before dosing (control), then at 5, 10, 15, 20, 25, 30,35,40,45,50,55,60,75,90 minand 2,3,4,5, 6, 7, 8 and 24 h after the start of the infusion. Urine collections were made as follows; control, 0-1, 1-2,2-3, 3-6,6-12, 12-24,24-48 and h after dosing. Oral dosing-blood samples were taken before dosing (control), then at 15, 30, 45, 60, 75, 90, 120, 150 min and 3, 4, 6, 8, 10, 12 and 24 h after dosing. Urine collections were made over similar periods to those after intravenous dosing. Inhalation-after the single dose, blood samples were taken before dosing (control), then at 2, 5, 10, 15, 30, 45 minand 1, 2, 3, 4, 6, 8 and 24 h after dosing. A similar sampling procedure was followed on the first and last day of the multiple dosing until the subsequent doses were taken. Sampling after these subsequent doses was at 15, 30, 45 min and 1, 2, 3 and 4 h. Detailed urine collections were made on blood sampling days. Twenty-four h urine collections were made throughout the multiple dosing period and until 72 h after the final dose. Patient study Subjects All patients entering the trial had a diagnosis of perennial extrinsic, intrinsic or mixed asthma. Patients were classified as extrinsic if one or more of the following were present: history or family history of allergic disease, positive skin tests or positive RAST (Radio-allergosorbent Test). Only in the absence of all these were patients classified as intrinsic. Of the total of 12, one had intrinsic and ten had extrinsic asthma; one patient, in whom the evidence was contradictory, was classified as mixed. In one subject asthma was described as severe, in one as mild and in the rest as moderate. Of the 12 subjects four were male and eight were female, with an age range of years and mean ± s.e. mean weight of 67 ± 3 kg. Pharmacokinetics of nedocromil sodium Treatment Patients received nedocromil sodium delivered by metered dose pressurised aerosol similarly to the volunteers. Each dose was of two actuations giving a total of 4 mg. For multiple daily dosing, two actuations four times daily were prescribed, giving a total daily dose of 16 mg. This is at the top of the therapeutic range which is two actuations two to four times daily (8-16 mg daily). Subjects were instructed to take only a single dose of 4 mg on Day 1 and to start the multiple dosing period of Day 2. Where blood sampling was carried out after multiple dosing (at 1, 6 and 12 months), subjects delayed the first dose of the day until they arrived at the hospital. Blood samples were then taken with timing in respect of this dose. Procedure Subjects fasted overnight only before the first dose. After control bloods and urines had been collected, dosing was carried out by the physician who aimed to actuate the aerosol at an early stage of a slow deep inspiration by each subject. The two actuations were administered with consecutive breaths. After each inspiration each subject was instructed to hold their breath for 10 s. Dosing was carried out in a room remote from the area where blood sampling was conducted. Blood samples (5 ml) were taken via an indwelling venous catheter before the dose and at 5, 10, 15, 20, 30, 40, 50, 60 and 90 min and 2, 3, 4 and 6 h afterwards. Urine was collected over the following periods after dosing: 0-6 and 6-24 h. After 1 month (28 days) subjects returned to the hospital without taking their morning dose. They brought with them a 24 h urine collection for the period immediately preceding the visit (i.e. for Day 27). A blood sample was taken by venepuncture immediately before administration of the morning dose by the physician and subsequent blood samples were taken 45 and 90 min after dosing. Subjects returned after 180 days (6 months) and 336 days (12 months) when a similar procedure to that after 1 month was repeated except that no urine was collected. Analysis ofsamples 495 Blood samples were centrifuged and the plasma was separated into heparinised tubes which were labelled, frozen and stored at -20 C until analysed. Aliquots of urine samples were similarly frozen and stored until analysed. Both plasma and urine were analysed by radioimmunoassay for content of nedocromil sodium (Gardner et al., 1987).

4 496 M. G. Neale et al. Pharmacokinetic analysis Pharmacokinetic parameters were evaluated using either the Bolt, Beranek and Newman RS1 software package or Nonlin (Metzler et al., 1974) on a VAX 11/780 computer. Area under the plasma curve (AUC) and plasma clearance were calculated by standard methods. The postinfusion intravenous plasma data were analysed using the method of Wagner (1975) for a two compartment open-model with elimination from the central compartment. The pharmacokinetic parameters derived from the intravenous data were then used in the analysis of the inhalation data using a two compartment open-model with two absorption components similar to that described for sodium cromoglycate (Neale et al., 1986). As the inhalation data were generated in different subjects from the intravenous data, the mean intravenous parameters were employed in the pharmacokinetic evaluation in the volunteers and the patients. No detailed pharmacokinetic modelling was attempted following oral administration. The terminal part of the concentration-time plot was used to yield a rate constant and associated halflife. Bioavailability, or extent of absorption, for the oral and inhalation routes was calculated (a) by comparison of the AUCs for the route with that for the intravenous route. (b) By comparison of the urinary excretion for the route with that for the intravenous route. For the oral route the bioavailability was evaluated in the same subjects as the reference intravenous dose; for the inhalation studies in both volunteers and patients the mean intravenous data was used to calculate the bioavailability. Results Intravenous The mean plasma concentration data obtained following intravenous infusion are illustrated in Figure la, whilst the derived pharmacokinetic parameters are shown in Table 1. Mean concentrations rose rapidly during infusion to reach a maximum of 13.7 ± 1.3 ng ml1' at the end of the infusion. After infusion ceased the concentration fell in a biphasic manner and by 6 h was below the level of detection (0.25 ng ml-). A good fit of the observed data to a two compartment model was obtained. Clearance of the drug from the plasma was consistently high in all subjects with a mean of 10.2 ± 1.3 ml min-' kg-'.... -e ' a Infusion ig6L 8 j_ 4i 0Oi b 8 c0 Co. CW Time (h) Mean ± s.e. mean plasma concentrations of Figure 1 nedocromil sodium in healthy volunteers after three different routes of administration: a, slow intravenous infusion-dose 6 tg kg-' over 30 min (n = 6); b, oral-dose lmg kg-' (n = 7); c, inhalation-dose 4mg(n = 6). a and b were the same group of subjects; c was a separate group. Table 1 Pharmacokinetic parameters of nedocromil sodium after intravenous infusion in six subjects at a dose of 6 pg kg-' over 30 min (Results expressed as mean ± s.e. mean) a (min-') ± (min-') ± Dose (mg) 0.41 ± 0.01 klo (min-1) ± k12 (min-1) ± k2l (min-') ± V1 (1 kg-') ± V&s (I kg-') ± AUC (ng ml-' h) 10.4 ± 1.2 Clearance (ml min-1 kg-1) 10.2 ± 1.3

5 klo (0.088 ± min-') was higher than,b (0.013 ± min-') (Table 1). 88 ± 1% of the total urinary excretion (80.7 ± 3.0% of the dose, Table 3) occurred within 90 min of cessation of the infusion; excretion thereafter was considerably slower with a half-life of 13.8 h (Figure 2). Oral After oral administration mean plasma concentration rose to a peak level of 5.8 ± 1.3 ng m-1' approximately 1 h after dosing (Figure lb). Concentration fell rapidly after the peak to 1.5 ± 0.2 ng ml-1 3 h after dosing and then declined slowly with a half-life of 21.1 ± 2.4 h. The key pharmacokinetic parameters are summarised in Table 2. The terminal portion of the Sigma minus plot of urinary excretion (Figure 2) had a half-life of 15.9 h, but only a small proportion (1.7 ± 0.3%) of the oral dose was excreted in the urine over 72 h (Table 3). Inhalation Plasma concentrations of nedocromil sodium after inhalation in volunteers are shown in Figure lc. The concentration rose rapidly to a level of 2.8 ± 0.6 ng ml-1 after 15 min, plateaued for approximately 1 h and then fell monoexponetially with a half-life of 2.3 ± 0.3 h. Pharmacokinetic parameters derived from the data are shown in Table 2. The Sigma minus plot of urinary excretion was biphasic (Figure 2); initially excretion occurred with a half-life of 1.2 h but after 6 h excretion continued more slowly with a half-life of 10.9 h. Total urinary excretion over 72 h amounted to 5.6 ± 1.0% of the dose (Table 3). Following multiple dosing in volunteers plasma concentrations showed a similar pattern to the Pharmacokinetics of nedocromil sodium 497 G1) 40 x Ur Time (h) Figure 2 Urinary Sigma-minus plots after different routes of administration. Results shown are mean s.e. mean for --c-- intravenous route (n = 6), * oral route (n = 7) and.v inhalation (n = 6). single dose (Figure 3) with only a small carryover. Urinary excretion during the multiple dose phase is shown in Table 4. During this phase daily individual excretion was variable but generally the mean excretion was greater than after a single dose. The overall excretion amounted to 12.0 ± 2.1% of the dose. The mean plasma concentrations of nedocromil sodium in patients following a single inhaled dose are shown in Figure 4. The mean concentration rose rapidly to a value of 1.7 ± 0.3 ng ml-' 5 min after dosing and thereafter showed little change over 90 min. In 10 of the 12 subjects there was no true peak, the pattern being one of a plateau. This was reflected in the variation in time to peak (tmax) which ranged from 5 to 90 Table 2 Pharmacokinetic parameters of nedocromil sodium after oral and inhalation administration in volunteers and patients (Results expressed as mean ± s.e. mean) Volunteers Patients Oral Inhalation Inhalation (n =7) (n = 6) (n = 12) Dose (mg) 70.5 ± Cmax (ng ml-') 5.8 ± ± ± 0.5 tmax (min) ± 6 40 ± 8 AUC (ng ml-1 h) 49.1 ± ± ± 0.6 ka* (h-1) ± ± ± 0.07 t½* (h) 21.1 ± ± ± 0.2 Urinary excretion (mg) ± ± ± 0.01t Bioavailability (%) from AUC 3.0 ± excretion 2.2 ± t * from the terminal part of the concentration-time plot. t n = 8.

6 498 M. G. Neale et al. Table 3 Urinary excretion of nedocromil sodium after different routes of administration in two groups of healthy volunteers Time % dose excreted in the urine after (h after Intravenous Oral Inhalation dosing) n =6 n =7 n= ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.0 Total 80.7 ± ± ± Day 1 Day 8 a E 04- C 0 0 E 0 4 Time (h) Figure 3 Mean + s.e. mean plasma concentrations of nedocromil sodium in healthy volunteers (n = 6) during multiple dosing. Data shown are for the first three doses and the last two of a 7 day multiple dose period at a dose of 4 mg four times daily by inhalation. 4 Table 4 Urinary excretion of nedocromil sodium during multiple inhalation dosing in volunteers (n = 6) Period Mean (± s. e. mean) % * excretion Single dose (0-72h) 5.6 ± 1.0 Multidose-Day ± ± ± ± ± ± ± 2.4 Final day 9.1 ± 1.7 Total 12.0 ± 2.1 * Calculated as % of each daily dose.

7 0 3 ~~~~Time Figure 4 Mean s.e. mean plasma concentrations of nedocromil sodium in asthmatic patients (n = 12) after a single inhaled dose of 4 mg. min. After 90 min there was a monoexponential decline in concentration with a mean half-life of h. The pharmacokinetic parameters are shown in Table 2; there were no significant differences between males and females. Urinary excretion (0-24 h) was % of the dose. 0) (h) However, this figure only represents the Pharmacokinetics of nedocromil sodium h excretion in eight of the patients because the co others began multiple dosing on the first day and the data for these subjects has been excluded. The mean plasma concentrations found in Co patients after multiple dosing are shown in Figure which shows also the relevant single dose data for comparison. On multiple dosing there was a small, but distinct, carryover which was similar throughout the dosing period. The patterns were similar at all times tested during the study, with E Time (h) FigureS Mean ± s.e. mean plasma concentrations of nedocromil sodium in asthmatic patients (n = 10) after multiple dosing. Day 1, Day 28, --o-- Day 180, TableDay 336. Significant difference (analysis of variance) from Day 1 is indicated by * P 0.001, + P0<±0.05. the differences from the single dose sometimes reaching statistical significance (analysis of variance) as shown. Mean 24 h urinary excretion in patients after 27 days dosing was 3.9 ± 0.7% of the dose. Because the intravenous pattern showed good consistency it was possible to use the data to allow curve fitting to the inhalation data even though the data was from different subjects. A flip-flop model was required to fit the inhalation data but, in addition, the two absorption rate model was used to accommodate the early rise to peak and plateau seen in both volunteers and patients. The rate constant for the fast absorption, ka1, was always high and was difficult to fit accurately because of the limited number of data points and the finding that large changes in kal made comparatively little difference to the fit. For consistency, therefore, kal was fixed at 1 which corresponds to an absorption half-life of < 1 min. The second, slower phase, corresponded to a half-life of 2.3 ± 0.3 h in volunteers and 1.7 ± 0.2 h in patients. Bioavailability The results (Table 2) show that oral bioavailability was 2 to 3% of the dose and was spread over a long period. For inhalation it was approximately 7-9% of the dose in volunteers but lower in patients. Discussion In order fully to understand the pharmacokinetics of a drug administered by inhalation it is necessary to study plasma concentrations and urinary excretion after intravenous and oral administration as well as after inhalation. Intravenous data yield information on distribution and elimination of the drug once it has been absorbed. Comparison of the inhalation data with the intravenous data yields information on the absorption process from the lungs. As a large proportion of an inhaled dose enters the gastrointestinal tract the contribution from this route also has to be measured and taken into account. Using such an approach and bearing in mind that the pharmacokinetics of nedocromil sodium are not complicated by metabolism (Brown, unpublished observations), we have studied the pharmacokinetics of nedocromil sodium in healthy volunteers and asthmatic patients although it was not possible to obtain data from oral, intravenous and inhalation routes in the same subjects. The pharmacokinetic results

8 500 M. G. Neale et al. obtained for nedocromil sodium are similar to those for sodium cromoglycate (Neale et al., 1986). This is not surprising as the two drugs have similar physico-chemical properties although their mechanism of action and therapeutic activity show differences (Eady etal., 1986; Auty, 1986). Our intravenous findings show a biphasic decline suitably fitted by a two compartment model However, the elimination from plasma into urine is extremely rapid and k1o > k12. Therefore the rate of excretion exceeds that of distribution so that during tissue distribution in the a phase the urinary excretion reflects closely the change in plasma levels. The terminal plasma half-life represents the rate-limited elimination from the tissues (Neale et al., 1986). With the Sigma minus plot for the intravenous route there are three phases: the first phase represents excretion; the second phase represents redistribution from the tissues; the terminal phase represents a third compartment which is presumably not picked up in the plasma analysis because of the limitations of the assay. The intravenous data show that nedocromil sodium is a drug with a high clearance, possibly even higher than with sodium cromoglycate (Clark & Neale, 1981). Nedocromil sodium is absorbed orally in man but only to a limited extent. The contribution of the oral component of absorption to the plasma picture after inhalation is small at the early time points (extrapolated peak oral concentration is 0.3 ng ml-' compared with 3 ng ml-1 for inhalation). Oral absorption, however, appears to continue over a prolonged period, presumably as the drug passes down the gastrointestinal tract. This could contribute to the prolonged urinary elimination profile after inhalation and also intravenous administration since at least 20% of an intravenous dose in man is eliminated in the bile (Brown, unpublished observations). Thus, the terminal half-lives of the Sigma minus plots for the oral, intravenous and inhalation routes are all similar. The results from the inhalation demonstrate that plasma concentrations rise rapidly, plateau and then decline with a half-life that is longer than that for the,-phase following intravenous dosing. The terminal half-life, therefore, represents the absorption half-life, absorption from the lungs becomes rate limiting and 'ffip-flop' kinetics apply (Gibaldi & Perrier, 1975; Neale et al., 1986). However, given the simple flip-flop model, the data do not fit very well particularly to the plateau part of the curve. By applying the model with more than one absorption component, as was done for sodium cromoglycate (Neale et al., 1986) a much better fit is obtained. Comparison of the pharmacokinetic data between patients and volunteers shows that peak concentration (Cmax) and AUC are lower in the former. Consistent with this, urinary excretion in the patients is lower but the patient data is limited. The results suggest that, whilst the pharmacokinetic profile in patients is similar to that in volunteers, the dose absorbed in patients is lower. The extent of absorption or bioavailability of nedocromil sodium after inhalation in volunteers is around 7-9% of the administered dose of 4 mg. This figure includes an element of oral absorption and if due allowance is made for this (2-3%) the extent of absorption from the respiratory tract comes to approximately 5-6% of the dose. Whilst this may appear low, it is not unusual for the inhalation route which at best yields up to 10% bioavailability (Newman et al., 1981). The relevance of the pharmacokinetics of nedocromil sodium to its efficacy will depend on the mechanism of action of the drug. Whilst this is not fully understood as yet (Shaw & Kay, 1985; Youngchaiyud & Lee, 1986) it is likely to be a topical effect on inflammatory cells within the lung. Therefore, a causal relationship between plasma concentration and therapeutic effect would not be anticipated as appearance in the plasma occurs after any effect has been produced. However, the plasma concentration will reflect both the rate and extent of absorption since absorption is rate limiting. The plasma concentrations observed in this study indicate that the drug persists in the lung longer than would be expected given the high clearance. Therapeutic activity with twice daily administration-the recommended clinical dose-may be indicative of this residence in the lung. We would like to thank Mr Derek Lowndes and staff of the Clinical Pharmacology Department for collection of the samples and Dr John Gardner and Mr Charles Gilbert of the Drug Metabolism Department for analysis of the samples. We also thank Mrs Gribben and the staff of the Chest Unit at Bury General Hospital for organisational assistance.

9 References Auty, R. M. (1986). The clinical development of a new agent for the treatment of airway inflammation: nedocromil sodium (TiladeO). Eur. J. resp. Dis., 69 (suppl. 147), Clark, B. & Neale, M. G. (1981). Hepatic and renal clearance of sodium cromoglycate. J. Pharm. Pharmac., 33, Eady, R. P., Greenwood, B., Jackson, D. M., Orr, T. S. C. & Wells, E. (1986). The effect of nedocromil sodium and sodium cromoglycate on antigeninduced bronchoconstriction in the Ascaris-sensitive monkey. Br. J. Pharmac., 85, Fairfax, A. J. & Allbeson, M. (1986). A double-blind group comparative trial comparing nedocromil sodium and placebo in the management of bronchial asthma. Eur. J. resp. Dis., 69 (suppl. 147), Gardner, J. J., Preston, J. R., Gilbert, C. M., Wilkinson, D. W., Lockley, W. J. S. & Brown, K. (1987). Radioimmunoassay of nedocromil sodium. J. Pharm. Biomed. Anal. (in press). Gibaldi, M. & Perrier, D. (1975). In Drugs and the Pharmaceutical Sciences, Pharmacokinetics, 1, 35, ed Swarbrick, J. New York: Dekker. Lal, S., Malhotra, S., Gribben, D. & Hodder, D. (1984). Nedocromil sodium: a new drug for the management of bronchial asthma. Thorax, 39, Lal, S., Malhotra, S., Gribben, D. & Hodder, D. (1986). An open assessment study of the acceptability, tolerance and safety of nedocromil sodium in long term clinical use in patients with perennial asthma. Eur. J. resp. Dis., 69 (suppl. 147), Metzler, C. M., Elfring, G. L. & McEwen, A. J. (1974). A package of computer programs for pharmacokinetic modelling. Biometrics, 30, Pharmacokinetics of nedocromil sodium 501 Neale, M. G., Brown, K., Hodder, R. W. & Auty, R. M. (1986). The pharmacokinetics of sodium cromoglycate in man after intravenous and inhalation administration. Br. J. clin. Pharmac., 22, Newman, S. P., Moren, F., Pavia, D., Sheahan, N. F. & Clarke, W. (1981). Deposition of pressurised aerosols in the human respiratory tract. Thorax, 36, Orr, T. S. C., Jackson, D. M., Greenwood, B., Wells, E. & Eady, R. P. (1986). Nedocromil sodium (Tilade@): a selective mucosal mast cell stabilizer. In Asthma: Clinical Pharmacology and Therapeutic Progress, ed Kay, A. B., pp Oxford: Blackwell Scientific Publications. Roberts, J. A. & Thomson, N. C. (1985). Attenuation of exercise-induced asthma by pretreatment with nedocromil sodium and minocromil. Clin. Allergy, 15, Ruffin, R. E. (1986). Nedocromil sodium: use in asthma. In Recent Advances in Airway Disease, ed Hargreave, F. E., pp Toronto: MES Medical Education Services. Shaw, R. J. & Kay, A. B. (1965). Nedocromil, a mucosal and connective tissue mast cell stabilizer, inhibits exercise-induced asthma. Br. J. dis. Chest, 79, Wagner, J. G. (1975). Fundamentals of Clinical Pharmacokinetics, ed Wagner, J. G., pp Hamilton, Illinois, Drug Intelligence Publications. Youngchaiyud, P. & Lee, T. B. (1986). Effect of nedocromil sodium on the immediate response to antigen challenge in asthmatic patients. Clin. Allergy, 16, (Received 30 January 1987, accepted 12 May 1987)

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