Eur J Clin Pharmacol (1992) 4 2 : 8 5 4 8

@ Springer-Verlag 1992

High dose oral methylprednisolone in patients with rheumatoid arthritis: pharmacokinetics and clinical response P. J. H a y b a l l 1, D . G. C o s h 1, M. J. A h e m 2, D . W. Schultz 2, and P. J. R o b e r t s - T h o m s o n 3 Pharmacy Department, z Department of Medicine, Repatriation General Hospital, Daw Park and 3 Department of Clinical Immunology, Flinders Medical Centre, Bedford Park, Adelaide, Australia Received: January 30, 1991/Accepted in revised form: June 19, 1991

Summary. A commercially available 1.0 g intravenous

(i.v.) dosage formulation of methylprednisolone, as the sodium hemisuccinate salt (Solu Medrol R, Upjoh'n) was administered both parenterally and orally (pulse steroid therapy) on separate occasions, to eight elderly (mean 65 y) patients with active rheumatoid arthritis. The relative oral bioavailability of the sterol was 69.2%. Elimination of methylprednisolone was prolonged when given orally; the mean residence times were 7.23 h and 3.94 h for oral and i. v. administrations, respectively. Clinical response to pulse steroid therapy was no different with respect to route of administration. There were no significant differences in standard clinical and laboratory assessments of disease activity when the two therapies were compared. Oral administration of methylprednisolone in patients requiring high-dose pulse steroid therapy is convenient and avoids the discomfort and inconvenience associated with i. v. administration. K e y words: Methylprednisolone, Rheumatoid arthritis; bioavailability, pharmacokinetics, clinical response, pulse steroid therapy.

Pulse methylprednisolone (MP) therapy has been used for several years as a treatment for active synovitis in patients with rheumatoid arthritis (RA). Previous studies have assessed the kinetics and response to conventional doses ( < 100 mg) of MP [1-5] or large boluses (viz 1.0 g) of intravenous (i.v.) MP [5-8]. Two studies [6, 7] have compared equivalent large doses of oral prednisolone with i.v. boluses of MP demonstrating similar clinical effects. Both studies used oral prednisolone administered as 40 tablets each of 25 mg strength. However, only Narang et al. [9] have examined high-dose oral MP and this was in comparatively young patients with RA with an age range of 33 to 51 y, and drug efficacy was not assessed in this study. We have re-examined the oral bioavailability of the parenteral MP drug product (no high-dose oral formula-

tion of MP is currently marketed in Australia) in those rheumatoid patients most likely to benefit from the convenience of oral MP yet where drug absorption and elimination is unknown. In addition, we determined the effect of high dose corticosteroid therapy given both orally and i. v. on clinical and serological disease parameters.

Materials and m e t h o d s

Subjects Ten patients with definite or classical R A (American Rheumatism Association criteria [10]) (8 m and 2 f) with a mean age of 64.8 y (range 50W6 y) and a mean duration of disease of 9.4 y were entered into the study. All patients had active disease: presence of three or more inflamed joints, morning stiffness of greater than 45 min duration and raised C reactive protein (CRP) or an erythrocyte sedimentation rate (ESR) greater than 30 ram- h 2. They had been treated with optimal doses of nonsteroidal anti-inflammatory drugs which were continued unchanged throughout this study. No patient was receiving treatment with oral corticosteroids at the time of entry into the study. Contraindications for entry into the study included prior use of intra-articular corticosteroids during the previous 8 weeks or change in slow acting anti-rheumatic drugs during the previous three months. Additional exclusion criteria were sepsis, active peptic ulcer disease, uncontrolled heart failure, labile hypertension and current anticoagulant therapy. The study was approved by the hospital's ethics committee.

Study design Each subject received a 1.0 g MP i. v. infusion (Solu-Medrol RUpjohn Co, USA) in 100 ml of 0.9 % sodium chloride for injection (Travenol Laboratories, Australia) over 30 rain. For oral administration the same i.v. preparation was diluted in 200 ml of orange cordial. The wash-out time between the i.v. and oral MP administration was 4 weeks. On each visit to hospital patients received both an i. v. infusion and an orange drink, one of which was the placebo. Treatment allocation was randomized by the method of Tukey [11]. Patients were observed for adverse effects after steroid administration. The development of any of the stated exclusion criteria or other adverse effect deemed serious enough to preclude further pulse steroid therapy resulted in withdrawal from the study.

E J. Hayball et al.: Methylprednisolone in rheumatoid arthritis

86 All other drugs taken by patients were recorded. Serum electrolytes, urea, creatinine, liver function tests and a complete blood picture were measured on each admission. Patients were fasted from the previous evening until 4 h after drug administration at 08.00 hours. Blood samples were collected into heparinized tubes via an indwelling intravenous cannula sited in the contralateral arm to that used for i.v. administration. Blood sampling took place immediately prior to each dose and then at 15 min intervals after the dose for the first h then at 30 min intervals for the next 2 h, hourly for the following 4 h and finally, 4 hourly up to 24 h post-dose. Plasma was stored at - 20 °C until analysis. Clinical responses were measured using an articular index of joint tenderness, duration of morning stiffness, and visual analogue scale assessment of pain. Clinical assessments on each occasion were made immediately prior to treatment and 24 h later. These were performed by a single assessor who was unaware of the treatment allocation. Blood serum samples were taken to determine CRP and rheumatoid factor (RF) using a laser nephelometer (Beckman ICS, USA).

Analysis of methylprednisolone Plasma concentrations of MP were measured by a specific high-performance liquid chromatographic method. The chromatographic system incorporated a Nova-Pak CN cartridge (10 cm x 8 mm ID; Waters Associates, USA) radially compressed with an RCM-100 compression module (Waters Associates) through which the mobile phase (20 % acetonitrile in distilled water) was pumped in an isocratic fashion at 1.5 ml-rain-1. The eluent was monitored at 240 nm for U V absorbance (Model 490, Waters Associates) and the system was maintained at room temperature (22°C). Prepared samples (see below) were injected onto the column via a Wisp Rautoinj ector (Waters Associates) and data handling and peak integration achieved with a Model 840 chromatographic data station (Waters Associates). Plasma samples (0.2 ml) were vortexed with 0.5 ml of acetonitrile containing internal standard (dexamethasone 2 mg. 1 1). Following centrifugation (2000 g for 5 min) the supernatant was eva-

porated to dryness under a stream of nitrogen at 45 °C prior to reconstitution with 0.25 ml of mobile phase and subsequent sample injection of 0.2 ml onto the column. The retention times for MP and internal standard were 6.5 and 7.4 min, respectively. These peaks were free of endogenous plasma-derived peaks and clear of methylprednisolone sodium hemisuccinate (MPHS) which eluted close to the column void time (approximately 2.5 rain). Calibration curves in the range 0.5 to 50 mg-1-1 were constructed as the peak-area ratios of MP to internal standard and generated in identical fashion to unknown plasma samples described above. Drng-free plasma was spiked with MP (Sigma Chemical Co., USA) and treated in identical fashion to subject sample unknowns (vide supra). Calibration curves were linear and passed through the origin. The mean normalized peak-area ratio was calculated for each set of standards and the coefficient of variation determined as a measure of intra-day assay performance. The mean (SD) coefficient of variation for 11 sets of calibration curves was 6.9 (2.6) %. The inter-day assay variability of the assay was determined by analyzing independent plasma standards at 2.50 and 10.0 mg.1 -~ levels; the mean (n = 11) coefficients of variation were 6.4% and 5.6 %, respectively. To determine whether ex vivo cleaving of MPHS to MP was occurring under conditions employed for sample storage; equimolar concentrations of the steroid and its ester pro-drug (equivalent to 10 rag/1 of the alcohol) in plasma were stored at - 15 °C and examined at biweekly intervals for 8 weeks for sterol content.

Pharmacokinetic methods The bioavailability (f) of the orally administered MP dose was estimated by f = AUCor,I/AUC~.v.,where AUCora~and AUQv. is the area under the plasma MP concentration time curve for the oral and i. v. 1.0 g doses, respectively. A U C was estimated in each case using the linear trapezoidal rule which was also used to measure the first moment of the plasma MP concentration-time curve (AUMC) after multiplying each plasma concentration by its time. A U C and A U M C were both extrapolated to infinity after performing least squares regression on the terminal portions of the

Table 1. Mean with (SD) and range pharmacokinetic and mean with (SD) clinical response parameters in patients (n = 8) receiving oral and i.v. methylprednisolone (1.0 g) on separate occasions Pharmacokinetic parameter

Route of administration Oral

Bioavailability tl/2 (h) MRT (h) Cmax (mg-1-1) tm~,(h) Cmax_2a (mg. 1-x) t~=_~b (h) e L (1- h 1)

69.2 (15.2) 4.93 (1.63) 7.23 (1.93) 9.17 (1.45) 2.17 (1.10) 7.25 (0.83) 4.30 (1.10)

i.v.

53.1-95.5 3.134.30 4.57-10.8 8.00-11.5 1.004.25 7.044.62 2.50-5.00

vss (1)

3.03 (0.59)* 3.94 (0.84)* 49.5 (31.9)*

2.34-3.80 2.86-5.15 20.747.2

9.01 (4.33) 31.8 (11.0)

4.84-17.2 20.8-53.9

24 h post-dose

Clinical parameter

Pre-dose Oral

i.v.

Oral

i.v.

Morning stiffness (min) Articular index VAS Pain (mm) CRP (mg/1) RF (i. u./ml)

115 (91) 27 (14) 52 (24) 71 (32) 601 (437)

110 (88) 26 (13) 59 (27) 74 (37) 663 (608)

28 (34)** 13 (14)** 24 (11)** 44 (31)** 557 (394)

31 (38)** 15 (8)** 25 (18)** 46 (35)** 658 (643)

a,b C . . . . z and t .... z refer to plasma MP concentration and corresponding time of the secondary rise in MP following the oral dose (observed in 5 of the 8 patients studied).

* Statistically significant differences (P < 0.01) between oral and i. v. parameters. ** Statistically significant differences (P < 0.01) between pre-dose and 24 h post-dose clinical parameters within a given dose route

87

E J. Hayball et al.: Methylprednisolone in rheumatoid arthritis

ration of morning stiffness, articular indices, visual analogue scales and CRP were lower at 24 h with both i.v. and oral MP (P < 0.01). At 24 h there were no differences between the two groups. There was no significant change in RF over 24 h. There was no evidence for ex vivo cleaving of the sodium hemisuccinoyl ester when examined under conditions employed for sample storage (up to 2 months at 15°C) and during sample preparation, prior to H P L C analysis. This suggests that storage conditions offered suitable protection against hydrolysis of the pro-drug which might otherwise give rise to spuriously high levels of sterol in those plasma samples obtained immediately following drug administration.

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Kinetic parameters

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Fig.1. Plasma concentration-time profile of MP following a 1.0 g dose of MP as MPHS (A = i.v. • = oral) in a single patient deemed representative of the study group

semi-logarithmic plasma concentrafion-time profiles. The mean residence time (MRT) was calculated for oral and i. v. regimens utilizing respective AUC and AUMC data according to: MRT= AUMC/AUC. The i.v. data were used to estimate the steady state distribution volume (V~0 and plasma clearance (CL) of MP expressed in terms of total (bound plus unbound) drug according to: V~ = C1.MRTi.v.and CL = Dosei.v./AUCi.~. The Wilcoxon matched pair signed ranks test was utilized to test for statistically significant differences in pharmacokinetic constants between routes of administration in each study patient and to assess the significance of changes in clinical and laboratory indices.

Results No patient was taking drugs reported to interfere with the metabolism of MP [12]. There were no electrolyte abnormalities and all patients had serum creatinine and liver function tests within the normal range when measured on both admissions. Two patients were withdrawn from the study. The first because of difficulties with venous access, while a second patient developed a recurrence of a depressive illness requiring psychiatric intervention after receiving i. v. MR Eight subjects completed the pharmacokinetic arm of the study (Table 1). All noted a bitter taste associated with the MP in orange cordial drink solution but apart from some mild facial flushing which proved to be independent of the route of administration, no other adverse effects were observed. The clinical measurements for the articular index, duration of morning stiffness and visual analogue scale for pain are summarized in Table 1. There were no differences in the clinical and laboratory parameters between the i.v. treatment and oral treatment periods at baseline. Du-

Plasma MP concentration-time profiles following i. v. and oral doses of the steroid are presented for a representative subject (Fig. 1). The mean (SD) oral bioavailability of the parenteral MP drug product administered as a 200 ml solution of MP in orange cordial was 69.2 % (15.2 %). The mean residence time and elimination half-life following oral dosing was significantly greater (P < 0.01) than respective i. v. values. The mean maximal plasma MP concentration (Cm~0 following i.v. administration of the hemi-succinate ester prodrug was approximately five-fold greater than the oral Cm~x.In 5 of the 8 study subjects a secondary rise in plasma MP was observed subsequent to the oral regimen. This rise occurred approximately 4 h after dosing and was not seen in any subject following i. v. MR

Discussion The absolute bioavailability of MP cannot be estimated since the pharmacologically active alcohol cannot be injected i.v. due to aqueous insolubility. Indeed approximately 10 % of i. v. administered MPHS (10 mg. kg- 1 MP) has been reported to be excreted unchanged in urine implying incomplete delivery of the alcohol from the prodrug [5, 8]. The possibility of as yet unidentified clearance of the ester other than generation of the parent MP would also need to be considered before absolute bioavailability could be estimated. Our estimate of the relative oral bioavailability of MP from the i.v. MPHS drug product is higher then the 49 % estimate obtained by Narang et al. [9] for 1.0 g of encapsulated MPHS. As we dissolved the ester prior to oral administration this might explain our improved bioavailability. Further, Narang et al. studied only 4 subjects and observed marked interindividual variation of this parameter (range: 13.7% to 85.7%). AIHabet and Rogers [3] reported an 82 % bioavailability following a 20 mg dose of MP alcohol tablets and given a 10% loss of MPHS in urine these low-dose data are in close agreement with our study. Antal et al. [2] also demonstrated similar bioavailability for 40 mg of MP administered as an oral solution of MPHS (73 % ) and 40 mg of MP as tablets of the alcohol (82 % ).

88 We observed a delayed terminal half-life and increase in the corresponding model-independent term (MRT) following oral 1.0 g dosing relative to the i. v. dose of the corticosteroid. Narang et al. [9] also observed this p h e n o m e na which has not been reported with low-dose studies. This apparent dose-dependent p h e n o m e n a leads to a slower rate of appearance of MP alcohol in plasma relative to the rate of elimination of the sterol from plasma. Possible explanations are; (1) absorption of the drug taking place along a large area of the small intestine thereby delaying the appearance of M P in plasma as a function of small intestine transit time, and (2) delayed in vivo hydrolysis of the pro-drug to the MP alcohol. While the extent of drug absorption was quite high and no significant oral lag-times were observed, the possibility of delayed ester hydrolysis cannot be excluded if such a process was occurring between the gut and the splanchnic blood flow. No such hydrolysis delays were observed from i.v. MP doses. It is feasible that the hydrolysis of orally administered M P H S was occurring by a different mechanism/rate to intravenously administered drug at the 1.0 g dose level and the involvement by intestinal flora in this process cannot be excluded given the observed secondary rises in plasma MP following oral dosing. These rises are consistent with possible enterohepatic cycling of the sterol, a similar observation having been made for 1.0 g oral doses of prednisolone [6]. To further characterize our observations we would have needed to administer MP alcohol via the oral route; such a dose product is unavailable in Australia. Further, we would need to determine plasma concentrations of MPHS. This was not possible with our H P L C system due to interfering peaks derived from endogenous plasma constituents. The observed clearance and distribution volume terms are in reasonable agreement with both previous high-dose i.v. and low-dose MP studies [3, 5, 8, 9]. Consistent with previous studies [6, 7] we have demonstrated a significant change in duration of morning stiffness, articular indices, visual analogue scales for pain and CRP at 24 h with both i.v. and oral routes. We have not determined whether there are any differences between the oral and i. v. route in regard to efficacy at 24 h as such a study would require a minimum of 56 patients, assuming a two-sided significance level of 0.05 and a power of 80 %. However, a previous study p e r f o r m e d by us has demonstrated that oral prednisolone has clinical and immunological effects equivalent to those of i. v. MP [7]. Also consistent with previous studies we have not shown any change in RF, although our study does not have the statistical power of these previous observations. In conclusion we have determined the relative oral bioavailability of a commercially available parenteral dosage form of M P H S in a group of elderly patients suffering from RA. Given the empirical nature in which the dose of 1.0 g of MP has been derived, and the emerging body of literature which supports the hypothesis that equivalent clinical responses can be obtained with lower doses of steroid [13],

P.J. Hayball et al.: Methylprednisolone in rheumatoid arthritis we would assert that the reduced bioavailability obtained with oral administration is unlikely to be clinically significant. Increased convenience afforded by oral as opposed to i. v. administration is a significant offsetting benefit.

Acknowledgments. We are indebted to Mrs. Mary Weatherall for performing clinical assessments and to Dr. Muriel Soden for her clinical assistance. We thank the nursing staff of ward 20 at the Repatriation General Hospital for their care of patients and adherence to the study protocol. We are grateful to Upj ohn Australia for their part sponsorship of this study. We thank the Department of Veterans Affairs for their support in carrying out this study.

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