technology: pharmacodynamic and pharmacokinetic implications

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1 Vol. 96 (2002)(SUPPLEMENT D), S9-Sl5 technology: pharmacodynamic and pharmacokinetic implications A. WOODCOCK, 1 D. ACERBI,~ G. POLIO North West Lung Research Centre, Manchester, U.K.; 2Chiesi Farmaceutici S.p.A., Parma, Italy Abstract In the drive to replace chlorofluorinated hydrocarbons (CFCs) by alternative more environmentally friendly propellants in pressurized metered dose inhalers (pmdls), Chiesi has developed new inhalers using Modulite@ technology. The aim was to obtain CFC-free pmdls which are equivalent, in terms of safety and efficacy, to the previous CFC devices at the same dose. When beclometasone dipropionate (BDP) and budesonide Modulite@ formulations were compared to the equivalent CFC products there was no significant difference in morning serum cortisol or urinary cortisol excretion, at the maximum recommended daily dose (2000 pg or I600 pg respectively). Single dose pharmacokinetic studies in both healthy volunteers and asthmatic patients compared systemic exposure (BI7MP levels) for BDP-CFC with BDP Modulite@ and extrafine BDP-HFA (QVAR@). Bl7MP levels for BDP-CFC and BDP Modulite@ were comparable, but substantially less than that seen with extrafine BDP-HFA After 6 weeks of treatment in asthmatic patients, B I7MP AUC after inhalation of BDP (I 000 pg twice-dally) from BDP Modulite@ was comparable with that obtained after BDP-CFC (Becloforte@). Plasma profile of BDP and B I7MP were similar after inhalation from BDP Modulite@ with standard actuator or delivered via a spacer; suggesting that pulmonary delivery of BDP to the lung is similar with both actuators Elsevier Science Ltd INTRODUCTION Inhalation is regarded as the preferred route for the treatment of airways disease because it delivers drugs to the site where they are needed. As a result, reduced doses can be administered, compared with systemic therapy, decreasing the potential for systemic exposure and improving the adverse-event profile.as a means of administering inhaled drugs, the pressurized metered dose inhaler (pmdi), rather than the dry powder inhaler, is currently the device of choice for asthma inhalation therapy. The pmdl is well-established as a safe and reliable delivery system and it is the device most widely used by adults with asthma (I), estimated to comprise around 68% of the total world-wide inhaled drug market. There are two major classes of inhaled therapy established for the treatment of reversible obstructive airways disease: bronchodilators and anti-inflammatory agents, generally steroids. Beclometasone dipropionate (BDP) and budesonide (BUD) are widely used topically active synthetic glucocorticosteroids. pmdls containing BDP or BUD with chlorofluorinated hydrocarbon (CFC) propellants (e.g. trichloro and dichlorofluoromethane) have been in use for more than 20 years. In the drive to replace CFCs by alternative more environmentally friendly propellants in pmdls, Chiesi Farmaceutici has developed new pmdl products using the Modulite@ technology. In Modulite@ pmdls, the drug is dissolved in the propellant, HFA I34a (Norflurane), with the aid of a co-solvent such as ethanol.the vapour pressure of the propellant, the proportion of co-solvent and the dimensions of the actuator orifice will largely determine the spray pattern from such a formulation. The final particle size distribution then depends on the drug concentration in a droplet and any other non-volatile components, which have been added.the permutation of these factors allows the design of a drug product with a chosen particle size distribution (2). The aim was to obtain hydrofluoroalkane (HFA) products therapeutically equivalent at equal doses in terms of safety and efficacy to the previous CFC devices. BACKGROUND INFORMATION ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF INHALED BDP AND BUD It is known that BDP is a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to the active metabolite

2 beclometasone- I7-monopropionate (BI 7MP) (3). The absolute bioavailability following inhalation of the CFC product is approximately 2% and 62% of the nominal dose for unchanged BDP and B I7MP respectively (4). Systemic absorption of unchanged BDP occurs mainly through the lungs with negligible oral absorption of the swallowed dose. The systemic absorption of B I7MP arises from both lung deposition and oral absorption of the swallowed dose. The bioavailability of orally administered BDP is negligible but pre-systemic conversion to BI 7MP results in absorption of approximately 40% of the swallowed portion as B I7MP There is an approximately linear increase in systemic exposure with increasing inhaled dose (S).The terminal elimination half-lives are 0.5 hours and 2.7 hours for BDP and B I7MP respectively (4). Plasma protein binding is moderately high; BDP is cleared very rapidly from the systemic circulation, by metabolism mediated via esterase enzymes that are found in most tissues (6). The main product of metabolism is the active metabolite (BI7MP). Minor inactive metabolites, beclometasone-2 I -monopropionate (B2 I MP) and beclometasone (BOH), are also formed but these contribute little to the systemic exposure. B I7MP metabolite is the most active with approximately 30 times the potency of BDP BI 7MP is also the most abundant metabolite in the plasma. Therefore the majority of the systemic corticosteroid effects will be related to B I7MP systemic exposure (7). BUD is a racemic mixture of R and S epimers. In vitro, no inter-conversion between the two epimers has been observed. BUD has a high relative affinity for the glucocorticoid receptor and the R epimer has 2-fold greater affinity than the S epimer (8). BUD is a moderately lipophilic compound that shows a rapid uptake into the airway mucosa. Although topical BUD is rapidly and extensively absorbed through the lung, there is no evidence of intrapulmonary drug metabolism apart from conjugation with fatty acids. In vitro tests did not demonstrate any oxidative or reductive metabolism of BUD by human lung homogenate. Budesonide is metabolized by cytochrome P450 3A in human liver (9). Elimination half-life was about 2.7 hours for both epimers after intravenous administration and a similar elimination half-life was observed after inhalation route.the oral bioavailability of BUD was about IO%, with approximately 90% of the dose subject to first pass metabolism in the liver (8). There is an approximately linear increase in systemic exposure with increasing inhaled dose from 400 to I600 ug (IO). BUD systemic absorption arises from both lung deposition, that may vary from IO to 30% depending on the device and user technique, and oral absorption of the swallowed dose. The systemic pharmacodynamic effects of BDP and its metabolites and BUD can be assessed by measuring the hypothalamus-pituitary adrenal (HPA) function that is a biomarker of the systemic activity of any exogenous corticosteroid, including those taken by inhalation. It has been well documented that doses up to 400 ug BDP in adults have no measurable effect on endogenous cortisol levels. The maximum recom- mended dose of BDP (2000 ug) does show reductions in endogenous cortisol of approximately 40% in healthy volunteers (5). Doses up to 400 ug day- of BUD via Turbuhaler@ have no measurable effect on endogenous cortisol levels in adult asthmatic patients (I I) while a minimal systemic effect on plasma cortisol (12) has been observed at 800 ug day -I; at I600 ug day -I, the maximum BUD adult dose, a transient reduction in endogenous cortisol of approximately 20% in asthmatic patients (I I) and of 41% in healthy volunteers observed. SYSTEMIC PHARMACODYNAMIC EFFECTS OF MODULITE@ FORMULATIONS (I 2) was The effect of BDP Modulite@ on the HPA axis has been compared with BDP-CFC (Becloforte@, GSK) 2000 ug (8 x 250 ug) in a crossover study conducted in I2 healthy volunteers (I 3). There was a similar reduction in serum cortisol (about 40% decrease) and in urinary cortisol excretion (45% decrease), for both treatments In a separate study, extrafine Baker Norton) (Figure I). BDP-HFA (Beclazone&, showed significantly greater 24h cortisol suppression than BDP-CFC (Becloforte@, GSK) after a single 2000 ug dose (5). The relative effect of BUD Modulite@ on HPA axis has been compared with that of currently available BUD inhalers products, Pulmicort@ CFC pmdl (BUD-CFC) and PulmicortTurbohaler@ (BUD-DPI) (Astra-Zeneca), in a three-way crossover, single dose study in I2 mild asthmatic patients (I 4). No difference in the serum cortisol concentration versus time curves (Figure 2) or in the urinary excretion has been observed. cortisol between the three different BUD formulations DOES PHARMACEUTICAL DATA PREDICTTHE SAFETY PROFILE? DATA FROM VOLUNTEERS In vitro characterization of aerosol formulations normally with Andersen Cascade lmpactor (ACI) is important in guiding pharmaceutical product development and is used in final quality control.the efficiency of delivery to the lung is dependent on particle size. It is generally agreed that particles below 4.7 urn reach the lungs while larger particles will deposit in the mouth and are swallowed ( I5,I6).

3 : PWPD IMPLICATIONS St I Cortisol in serum -RUN-IN Normalized cortisol excretion in urine *-* BDP-CFC (Glaxo) --. BDPModulite 0 / I I I I I RUN-IN BDP-CFC BDP Modulite@ Time The central line in each box represents the median value; the upper and the lower lines represent the 7P and the 25 percentiles. The bars represent the minimum ond nuximum values FIGURE I. Mean serum cortisol profile and urinary excretion (normalized for urinary creatinlne) in healthy volunteers (n= 12) after Inhalation of a single 2OOOpg dose of BDP Modulitem and BDP-CFC 1 o--o BUD-CFC - BUD-DPI k+ BUD Mod&@ t (-2M rhroat <IO <9 <5.8 c4.7 <3.3 <2.1 Cl.1 <o-7 <0.4 Andersen Cascade Impactor Cut-off (pm) FIGURE 2. Mean serum cortisol profile in mild asthmatic patients (R = I 2) after inhalation of a single I 600 pg dose of BUD Modulitem. BUD-CFC and BUD-DPI. BDP Twelve healthy volunteers were enrolled into a single IO00 ug dose, three-way crossover, pharmacokinetic study of three different BDP pmdl formulations: BDP Modulite@ with spacer (Jet@) (Beclojet@ 250) MMAD (mean mass aerodinamic diameter) 26 urn, extrafine BDP-HFA (QVAR@ 100, 3M Pharmaceuticals) MMAD I.2 pm, Chiesi BDP-CFC with spacer (Jet@) (Clenil Forte@ 250) MMAD 4.7 urn (I 7) (Figure 3). The area under the concentration-time curve (AUC) for BDP and its metabolite BI 7MP were assessed following inhalation from each pmdl product.the AUC calculated for BI 7MP during the first hour after inhalation AUC(,,,) and BDP AUC,,,, (calculated up to the last measurable plasma concentration) were likely to reflect lung rather than gut absorption, since BDP is rapidly metabolized to B I7MP in the lung.the AUCs for BDP and BI 7MP were significantly greater with the extrafine BDP-HFA formulation than with the BDP-CFC and BDP Modulite@ Jet@ formulations (Figure 4). BDP from the extrafine BDP-HFA pmdl was more raoidly absorbed into the systemic circulation as r FIGURE 3. Distribution of BDP in the Andersen Cascade lmpactor stages. shown by BI7MPAUC~a_,,).The change in MMAD from 4.7 urn to 2.6 urn had a negligible influence on BDP absorption, with AUCs for BDP and BI 7MP only slightly increased, while the change in MMAD from 2.6 pm to I.2 urn was associated with a marked increase in absorption. A relationship was seen between the amount deposited in the ACI stages 3 to 6 (aerodynamic diameter between 4.7 and 0.7 urn) and AUCs (Figure 5). The in vitro and pharmacokinetic data suggest that from the safety viewpoint the transition from BDP-CFC to BDP Modulite@ can occur without any dose adjustment. BUD The systemic exposure to BUD epimers, following a single inhalation of I600 ug (8 x 200 pg shot- ), from two BUD Modulite@ pmdls with different orifice diameter (0.30 and 0.42 mm) was assessed in six healthy volunteers (I 8). The fine particle dose (FPD < 4.7 pm) for both epimers is higher with the 0.30 mm compared with the 0.42 mm orifice (29. I vs UP for eoimer R.

4 Sl2 MEDICINE O.SO Timelhl FIGURE 4. BDP and B I7MP median Dlasma levels In I2 healthy volunteers after a IO00 pg dose. I L 800 f B 600, /,,,,,li./ /,/,/ s 400 d 200 0, --- /--,I,,, _/.* )_---e I i(il FIGURE 5. RelationshIp between median AUCs of BDP and B I7MP vs MMAD and BDP recotier-ed In stage 3 lo 6 AC1 R epimer 100 S epimer <IO X S4.1 S l SO.7 SO.4 Andersen Cascade Impactor Cut-off (pm) <IO G-4 Andersen Cascade Impactor Cut-off (pm) FIGURE 6. Distribution Modulite@ formulation. of R and S budesonide eplmers It- the Andersen Cascade lmpactor stages after ten cumulative shots oi BlJilj and 19.7 vs. I I.4 pg for epimer S respectively) and the MMAD was slightly lower with the smaller orifice (3. I pm, vs. 3.5 pm) (Figure 6). BUD plasma levels peak immediately after administration and reflect mainly lung absorption. Overall BUD bioavailability was 30% (S epimer) and 40% (R epimer) higher using the actuator with the smaller orifice, suggesting that an increase in the FPD increases the peripheral lung deposition with consequent higher systemic absorption. However, absorption rate and elimination half-life were unaffected by the change in the orifice diameter with the exception of a slightly reduced elimination half-life of S epimer (Figure 7). The choice of a different actuator orifice allows modulation of the fine particle dose to provide Modulite@ HFA pmdls matching different marketed BUD inhalers. SYSTEMIC EXPOSURE IN PATIENTS The pharmacokinetics of BDP after inhalation from BDP Modulites have been compared with a reference

5 : PWPD IMPLICATIONS Sl3 R epimer S epimer w BUD Modulite@ 0.30 w BUD Modulne@ 0.30 c-a BUD ModulitG O.42 t+ BUD Modulite@ I IO II II I2 FIGURE 7. BUD epimers median plasma levels in six healthy volunteers after inhalation of a I6OOFg dose of BUD Modulite pmdls with different orifice diameter (0.30 and 0.42 mm). BDP-CFC product (Becloforte@, GSK) in adult patients with moderate-to-severe persistent asthma (I 9). Thirty-two adult patients with moderate/severe asthma entered a double-blind, double-dummy, randomized, parallel-group study.they were randomly assigned to 2000 pg BDP daily (1000 pg twice-daily) from either BDP Modulite@ or BDP-CFC both inhaled via a spacer device (Volumatic@, GSK). Pharmacokinetic sampling was carried out after 6 weeks of treatment following the last morning administration.twenty-eight patients (I3 male and I5 female) completed the pharmacokinetic study. Unchanged BDP plasma levels were very low, and below the detection limit shortly after inhalation; therefore the pharmacokinetic evaluation was performed for the active BI 7MP metabolite only.the total systemic exposure to B I7MP represented by the plasma AUC over the dosing interval (AUC,) at steady-state in asthmatic patients, after inhalation of BDP (I 000 pg twice-daily) from BDP Modulite@ (AUC,: 2 I24 pg ml -1 h) was comparable with that obtained after BDP-CFC (AUC,: 2 I60 pg ml -I h). The small difference observed in the initial absorption rate for BI 7MP with a higher C,,, and an earlier T,, with BDP Modulite@ appears to be due to a rapid initial absorption rate from the lung, rather than a difference in pulmonary deposition, since the plasma AUC values are comparable (AUC, ratio: 0.98) (Figure 8). The difference in C,,, observed for the Modulite@ product is unlikely to result in differential pharmacological effects, since the systemic effects of corticosteroids (such as HPA axis suppression) are correlated with the total systemic exposure rather than peak concentrations (20). In contrast to these findings, the AUC and C,,, for BI 7MP obtained with both extrafine HFA formulations of BDP (QVAR@ and Beclazone@) have been reported to be between two and three times higher than the CFC reference product (5,2 I). --. Beclofort@ (n = 12) o-0 BDPModulW (n = 14) 0 I FIGURE 8. B I7MP mean (SD) plasma concentration-time profiles for asthmatic patients at steady-state after IO00 pg BDP twice-daily from either BDP Modulite@ or BDP-CFC. INFLUENCE OF CHARCOAL BLOCK AND OF A SPACER DEVICE ON PULMONARY DEPOSITION AND SYSTEMIC EXPOSURE The effects of a charcoal block and the use of the spacer (let@) on the absorption of BDP and BI 7MP after BDP Modulite@ have been studied in six healthy subjects after inhalation of a single dose of BDP (1600 pg), using a crossover design (22). BDP and B I7MP plasma levels were determined over a I2 hours period.the charcoal block did not affect the plasma levels of BDP, confirming that BDP found in the systemic circulation arises almost entirely from BDP absorbed unchanged from the lung, and that swallowed BDP is not bioavailable due to the pre-systemic conversion to BI 7MP As regards BI 7MP plasma levels, these were only slightly reduced (less than 20%) by the charcoal block, confirming that the pulmonary absorption is the main source of systemic exposure to BI 7MP The BDP and B I 7MP plasma profiles after inhalation from BDP Modulite@ with standard actuator or from the same formulation delivered via the spacer were virtually

6 BDP s 075 I.oo I.25 I h x IO 11 Ii lh Time(h) FIGURE 9. Plasma BDP and B I7MP following Inhalation of BDP Modulate W / 600 kg with or- without ~harcodl bloci~ and with space:- (JetTM) (median ~6). identical, suggesting that pulmonary delivery of BDP to the lung is similar with and without spacer (Figure 9). CONCLUSIONS The Modulite@ formulations of inhaled steroids in HFA are equivalent, in term of safety, to the marketed (CFC and DPI) inhalers. The extent of cortisol suppression evaluated in healthy volunteers and patients using the maximum recommended dose (2000 pg BDP and 1600 bg BUD) was comparable for both corticosteroids. The similarity of the systemic pharmacodynamic effects produced by the products is consistent with the in-vitro data. By combining Modulite@ formulations with different orifice diameters, it has been possible to manipulate the fine particle dose so that they closely match currently available inhalers. Systemic exposure for Modulite@ formulations are comparable with CFC products at the same dose. Pharmacokinetic studies performed, in both healthy volunteers and in asthmatic patients, using the standard actuator and an actuator incorporating a spacer demonstrated that the systemic exposure was comparable for Modulite@ inhaler and CFC inhaler. Systemic exposure of BDP Modulite@ is substantially less than for the extrafine BDP-HFA pmdl (QVAR@ 3M) for which an adjustment of the dose is required. After BDP Modulite@ inhalation, the systemic exposure of BDP is unaffected by the spacer device and only slightly reduced by the charcoal block, confirming the optimal lung deposition of the corticosteroid. REFERENCES Woodcock A. CFCs and inhalers. Loncet 1994; 344: I Ganderton D, Lewis DA, Meakin Bj, Brambilla G, Garzia R,Ventura I? Pharmaceutical aerosol composition. WO Patent Application 1998; no Martin LE,Tanner RJN, ClarkTJH, Cochrane GM, et of. Absorption and metabolism of orally administered beclometasone dipropionate. Clin Phormocol Ther 1974; I5(3): Daley-Yates PT, Price AC, Sisson J R.. Pereira A, Dallow N, er ai. Systemic bioavailability of beclometasone dipropionate (BDP) following inhaled, intranasal, oral and intravenous dosing in man. Eur Respir j 2000; I 6(3 I ): 280s. 5. Daley-Yates PT. Baggen S. Tournant J, Pereira A. Beclometasone dipropionate chlorofluorocarbon and hydrofluoroalkane metered dose inhalers: relationship between systemic exposure. dose, fine particle mass and particle size in healthy volunteers. Eur Respir j 199% I4(30): 196s. 6. Wurthwein G. Rohdewald P Activation of beclometasone dipropionate by hydrolysis to beclometasone - I7-monopropionate. Biophorm Drug Dispos 1990; I I : 38 I Boobis AR. Comparative pysicochemical and pharmacokinetic profiles of inhaled beclomethasone Respir Med I998 ; 92(B): 2-6 dipropionate and budesonide. 8. Donnelly R, Seale PJ. Clinical pharmacokinetics of Inhaled budesonide. Clin Phormocokinet 200 I: 40(6): Jansson G,AstrGm A,Andersson P Budesonide is metabolized by Cytochrome P450 3A (Cyp3A) enzymes in human liver. Drug Metob Dispos 1995; 23(l): IO. Kaiser H,Aaroson D. Dockhorn R, Edsbacker S, Korenblat P, Kallen A. Dose-proportional pharmacokinetics of budesonide inhaled via TurbuhaleP. Br j Cfin Phormocol 1999; 48: I I. Derom E,Van Schoor J,VerhaegheW,Vincken W, Pauwels R. Systemtc effects of inhaled fluticasone propionate and budesonide in adult patients with asthma. Am J Respir Crit Care Med 1999; 160: 157-l 6 I 12. Donnelly R, Williams KM, Baker AB, Badcock CA, Day RO, Seale JP Effects of budesonide and fluticasone on 24-hour plasma cortiso1.a dose response study.amj Respir Crit Care Med 1997; 156: I Knops A, Bendahmane S. Nollevaux F. Open randomized, two-way 75 I crossover, comparative study of two metered dose inhalers of beclometasone dipropionate after single dose in twelve healthy male subjects. (Study SGS B , Data on file) 14. Frank B, Knops A, Simonon A. Open randomized, three way crossover comparative clinical pharmacology study of one new HFA metered dose inhaler of budesonide and two different marketed products CFC MDI (Pulmicort@) and DPI (Pulmicort Turbohale@) after single dose of 1600 pg in twelve asthmatic patients. (Study SGS BI 0 I57 I, Data on file) 15. Zanen i? Go LX Lammers JJ. Optimal particle size for P-adrenergic aerosols in mild asthmatics. Int ] Phorm 1994; IO7(3): 2 I l Poutler LW. Central inflammation is more important than peripheral inflammation. Respir Med 1997; 9 I (Suppl A): Acerbi D. Deroubaix X. De Bruyn S. Poli G,Ventura I? In vitro-in viva correlation study of three metered dose inhalers of beclometasone dipropionate. Respiratory Drug Delivery VII 2000;

7 : PWPD IMPLICATIONS Sl5 I& Acerbi D, Deroubaix X, De Bruyn S, Poli G, Zanol M, Magi N, et al. Biopharmaceutical optimisation of a new CFC-free budesonide pmdi. Respiratory Drug Delivery VIII 2002; Acerbi D, DaleyYates PT Poli G,WoodcockA. Langley SJ. Pharmacokinetics of a new CFC-free metered dose inhaler of beclometasone dipropionate following multiple dosing in asthmatic patients. Respiratory Drug Delivery VIII 2002; 89-9 I. 20. Thorsson A. et al. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. Brj Clin Phormacol 1997; 43: I. Lipworth BJ, Jackson CM. Pharmacokinetics of chlorofluorocarbon and hydrofluoroalkane metered dose inhaler formulations of beclometasone dipropionate. Br 1 Clin Pharmacol 1999; 48(6): Knops A, Bendahmane S, Nollevaux E Pilot open randomized, three- way crossover, comparative lung absorption study of a BDP CFC- free metered dose inhaler in six healthy male subjects. (Study SGS B I005 12, Data on file).