Drug Evaluation

Drugs 39 (5) 741-756, 1990 0012-666 7/90/0005-0741/$08.00/0 © ADIS Press Limited All rights reserved. DREND2102

Inhaled Pentamidine

An Overview of its Pharmacological Properties and a Review of its Therapeutic Use in Pneumocystis carinii Pneumonia

Jon P. Monk and Paul Benfield ADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: W. Brumfitt, The Royal Free Hospital, London, England; P.-M. Girard, H6pital Claude Bernard, Paris, France; I.A. HoogkampKorstanje, Laboratory for Public Health, Leeuwarden, The Netherlands; S. Lang, MiddIem ore Hospital, Auckland, New Zealand; A.B. Montgomery, School of Medicine, State University of New York at Stony Brook, Stony Brook, New York, USA; M.J. O'Doherty, St Thomas' Hospital, London, England.

Contents

Summary .................................................................................................................................... 741 I. Overview of Antiprotozoal Activity .................................................................................... 743 2. Pharmacokinetic Properties ........................ ......................................................................... 744 2.1 Parenteral Administration ........... ............ ..................................... ................................. 744 2.2 Aerosol Administration ................................... ....... ..................... ... .......... ..................... 744 2.2.1 Absorption from the Lungs .................................................................................. 744 2.2.2 Deposition in the Lungs ....................................................................................... 745 2.3 Aerosol Formulations and Particle Size ....................................................................... 746 3. Therapeutic Trials ............................................................. .................................................... 747 3.1 Treatment of PCP .......................................................................................................... 747 3.2 Prophylaxis of PCP ........................................................................................................ 748 4. Adverse Effects ...................................................................................................................... 751 5. Dosage and Administration ................................................................................................. 753 6. Place of Inhaled Pentamidine in the Management of PCP .............................................. 754

Summary Synopsis

P('ntamidin(' is an aromatic diamidin(' d('rivativ(' which has b('com(' on(' of the standard th('l'api('s for Pneumocystis carinii pneumonia (PCP). particularly in patients with acquir('d immunod(,/ici('ncy syndrom(' (AIDS). However. with par('nteral administration of th(' drug th('r(' is a high risk of toxicity. Inhaled pentamidine produc('s much higher conc('ntrations of drug on the bronchoalv('olar surface with minimal systemic absorption. It has b('r'n us('d successfully for th(' trmtm('nt of PCP in AIDS patir'nts. but its most l'aluabl(' contribution has b('en as prophylaxis in AIDS patients at high risk of d('v('loping pCP. In prosp('ctiv(' controll('d studi('s th('l'(' has be('n > 80% reduction in relaps(' rate with p('ntamidin('. Th(' r('duction in relaps(' rate among pati('nts who have ('xperienced one pr('vious ('pisod(' of pCP has b('('n 50 to 100% compared with historical control groups.

742

Drugs J9 (5) 1990

over a follow-up period averaging about 6 months. Significant systemic adverse effects to inhaled pentamidine are rare. Respiratory effects associated with inhalation are common but usually controllable without treatment discontinuation. The ideal particle size for even distribution ofpentamidine throughout the lung is considered to be I to 2/-lm. Jet nebulisers such as the 'Respirgard II'system produce a mass median aerodynamic diameter (MMAD) of particles in this range. Ultrasonic nebulisers produce larger particles. The implication from this difference is that while ultrasonic nebulisers may have poorer alveolar distribution and the incidence of local side effects (common with all formulations) may be higher, total drug delivery may be more efficient allowing effective PCP prophylaxis with lower dosages (J 20mg vs JOOmg monthly). However, there are no data available comparing the efficacies and IOlerabilities of the different formulations of inhaled pentamidine. Nevertheless, inhaled pentamidine would seem poised to become routine prophylaxis in patients with AIDS or AIDS-related complex at risk of developing PCP.

Antiprotoloal and Pentamidine has been reported to have a destructive action against P. carinii in vitro, Pharmacokinetic Properties reducing its viability to a similar extent as trimethoprim-sulfamethoxazole. After parenteral administration pentamidine becomes widely distributed and is strongly tissue bound, with highest concentrations achieved in the liver and kidney and lower levels in the lung and other tissues but not in the brain. Pentamidine is detectable in some tissues up to a year after the last dose of a course of parenteral therapy. After aerosol administration pentamidine is rarely detectable in the plasma, but bronchoalveolar concentrations are 5 to > 10 times higher than after intravenous administration. A variety of jet and ultrasonic nebulisers have been used to administer aerosolised pentamidine. Important differences between them would seem to be the mass median aerodynamic diameter of particles produced and the efficiency of total drug delivery. Smaller particles «2f.Lm) have a more uniform distribution throughout the lung, while greater deposition of larger particles in the large airways may be associated with bronchospasm. Therapeutic Trials

For the treatment of mild PCP (usually first episodes) in AIDS patients the results of clinical trials with inhaled pentamidine have been encouraging, particularly with the 'Respirgard II' nebuliser, 300 or 600mg daily for up to 21 days; the success rate has ranged from 81% to 100%. There is considerably more evidence available to support the use of inhaled pentamidine as prophylaxis in patients at high risk of developing PCP. Many of the reported studies have included over 100 patients, with the mean follow-up time ranging from 4 to 10 months, and follow-up continuing for 18 months in some patients. Maintenance dosages of pentamidine ranged from 60 to 300mg per month delivered through a variety of aerosol formulations. The incidence of PCP recurrence during pentamidine prophylaxis was consistently low (6 to 16%). In two prospective studies which included control groups there was over 80% suppression of PCP episodes with pentamidine. A dose comparison study using the 'Respirgard II' nebuliser revealed significantly better prophylaxis with a dose of 300mg once monthly (6.2% recurrence) than with 30mg bimonthly (18.8%). However, using the 'Fisoneb' formulation or other ultrasonic nebulisers, dosages of ~ 120mg monthly (usually 60mg every 2 weeks) provided effective prophylaxis with PCP recurrence rates in the range 5.9 to 16%.

Adverse Effects

No significant systemic effects definitely attributable to inhaled pentamidine have been reported in clinical trials, in marked contrast to the poor toxicity profile of parenterally administered pentamidine. However, there have been isolated reports of pancreatitis, maculopapular rash, hypoglycaemia and pneumothoraces. Also, there have been reports of atypical pulmonary P. carinii infection and extrapulmonary pneumocystosis in patients receiving inhaled pentamidine. Cough and bronchospasm have been common

743

Inhaled Pentamidine: A Review

during inhalation, but can usually be controlled by reducing the delivery rate or intensity of the aerosol stream and/or by pretreatment with a bronchodilator. Dosage and Administration

Various ultrasonic and jet (flow rate about 6 L/min) nebulisers have been used successfully for prevention of PCP in high-risk human immunodeficiency virus (HIV)-positive patients. The recommended dosage of inhaled pentamidine, employing a jet nebuliser delivering particles of small size (e.g. 'Respirgard II'), is a single 300mg dose every 4 weeks. However, with ultrasonic nebulisers delivering larger particles successful prophylaxis has been demonstrated with a dosage of 60mg twice monthly.

Pentamidine, an aromatic diamidine derivative with antiprotozoal activity, was developed about 50 years ago. It has received renewed interest in recent years following the resurgence of Pneumocystis carinii pneumonia (PCP) in patients with acquired immunodeficiency syndrome (AIDS). After parenteral administration pentamidine is associated with frequent and occasionally severe adverse reactions (Goa & Campoli-Richards 1987; Salamone & Cunha 1988), thus inhaled administration has been studied with the aim to achieve higher drug concentrations at the site of infection and minimise problems of toxicity. Pentamidine is manufactured as isethionate and mesylate salts. For the isethionate salt 1.74mg is equivalent to Img pentamidine base, while 1.56mg of the mesylate salt is equivalent to Img pentamidine base. However, pentamidine isethionate is labelled by the manufacturer to reflect the weight of salt but pentamidine mesylate is labelled to reflect the weight of pentamidine base. Thus, a dose of 2.3 mg/kg as the mesylate salt is equivalent to 4 mg/kg as the isethionate salt (Arnott et al. 1988; Centers for Disease Control 1984). There is evidence that hypoglycaemia occurs more frequently with the mesylate salt, when administered parenterally (Be1ehu & Naafs 1982). The isethionate salt is by far the predominant form used in clinical studies, and its chemical formula is shown in figure 1. Unless

Fig. 1.

Structural formula of pentamidine isethionate.

otherwise specified this review refers to pentamidine isethionate.

1. Overview of Antiprotozoal Activity Pentamidine (0.3-9 mg/L) decreased the viability of P. carinii to a similar extent as trimethoprim/sulfamethoxazole (1.8-54/9-270 mg/L), in experimental models in chick embryo lung epithelial cells (Pifer et al. 1983) and lung cells of rats with pneumonia induced by corticosteroids (Pesanti 1980) or cultured from WI-38 cells (Bartlett et al. 1983). The action of pentamidine has been reported to be 'cidal' rather than 'static', but the exact mechanism of its effect on P. carinii is unclear. It may interfere with oxidative phosphorylation and nucleic acid synthesis, inhibit glucose metabolism and other functions (without influencing protein synthesis or amino acid transport), or it may inhibit dihydrofolate reductase (Goa & CampoliRichards 1987). The standard in vivo model used to investigate activity against P. carinii is PCP induced in rats by corticosteroid immunosuppression. Parenteral administration of pentamidine has not revealed great success, as reviewed by Goa and CampoliRichards (1987). Recently, however, 2 studies have reported substantial success rates with pentamidine aerosols in the treatment and prophylaxis of PCP in rats (Debs et al. 1987; Girard et al. 1987). At a dose of 5 mg/kg/day for 2 weeks inhaled pentamidine, in free form or encapsulated in liposomes, eradicated PCP in 75% of the animals treated (Debs et al. 1987). Girard et al. (1987) revealed a dose-related effect, with little benefit at a dose of 4.7 or 6 mg/kg of pentamidine mesylate 3

744

Drugs 39 (5) 1990

times per week for 3 weeks, but eradication in 70% of animals at a dose of 14.6 mg/kg according to the same schedule. When pentamidine prophylaxis was started at the same time as immunosuppression, a dose of 8.6 mg/kg 3 times per week prevented infection in all animals, as did trimethoprimjsulphamethoxazole 40/200 mgjkg twice weekly, subcutaneously; all control animals developed PCP (Girard"et al. 1987).

2. Pharmacokinetic Properties 2.1 Parenteral Administration Following intravenous administration of pentamidine 4 mg/kg to patients with AIDS the peak plasma concentration is usually 0.2 to I mg/L (Bernard et al. 1985; Conte & Golden 1988; Conte et al. 1986). Tissue binding is strong and the volume of distribution of pentamidine is about 3 Ljkg (Otterness et al. 1978). Data on the distribution of the drug in humans are limited. Donnelly et al. (1988) used a bioassay method to measure the drug concentration in autopsy specimens from AIDS patients who had received pentamidine ("" 4 mg/ kg) parenterally for 2 to 33 days. In 4 patients who had received moderate total doses (1 OOO-1400mg), average tissue concentrations were (J.l.gjg): liver, 134; kidney, 73; adrenal, 52; spleen, 37; lung, 30; brain, < 0.8. Thus, with parenteral administration penetration of pentamidine into lung tissue is relatively poor. Slow release of pentamidine from tissue compartments means that elimination is prolonged. The autopsies of some of the AIDS patients studied by

Donnelly et al. (1988) revealed detectable concentrations of pentamidine in tissues up to a year after the last dose. Pentamidine is excreted virtually unaltered via the kidney (Waalkes & DeVita 1970), and can also be detected in urine for up to a year after the last course of therapy (Waalkes & Maluku 1976). 2.2 Aerosol Administration Two factors of particular importance when considering aerosol administration of pentamidine are the total amount of drug delivered to the lungs and the distribution of deposition within the lungs. Current evidence suggests that these factors are related to the efficiency of drug d~livery by the aerosol and the particle size produced in the aerosol, and are thus dependent on the type of aerosol used. Section 2.3 describes the properties of some of these aerosols. 2.2. J Absmption from the Lungs Plasma concentrations of pentamidine after aerosol administration have been monitored rarely. Montgomery et al. (1988) recorded a detectable concentration (13 J.l.gjL) in only 1 of 5 AIDS patients at the end of inhalation of 300mg pentamidine over 35 to 40 minutes ('Respirgard II'). The maximum individual concentration recorded at the end of inhalation of 4 mgjkg over 30 to 75 minutes from an ultrasonic nebuliser in 5 patients was only 7 J.l.gj L (Girard et al. 1988a). A later study by Girard's group (Girard et al. 1989c) compared plasma concentrations of pentamidine in spontaneously

Table I. Plasma concentrations of pentamidine after intravenous or inhaled administration for 2 to 18 days in patients with PCP (Conte & Golden 1988) Route of administration

Dosage (mg/kg/day)

Intravenous

3-4

Inhaled b

4

a b

No. of patients

Peak plasma concentration ("g/L)a mean

range

3

260 ± 88.2

169-345

13

13.8 ± 11.9

0-35

At the end of intravenous infusion or inhalation. 'Ultravent' nebuliser, using a compressed airflow and inhalation of 4 mg/kg over 30 to 45 minutes.

Inhaled Pentamidine: A Review

745

Table II. Concentrations of pentamidine in bronchoalveolar lavage from the right middle lobe approximately 24 hours after drug

administration intravenously or by inhalation in patients with suspected or confirmed PCP Reference

Route of administration

Dose

No. of patients

Bronchoalveolar concentration (I'g/L)

Conte & Golden (1988)

Intravenous Inhaled

3-4 mg/kg 4 mg/kg b

4 8

6.05-21.4 a 28.6-177.5 a

Montgomery et al. (1988)

Intravenous Inhaled

4 mg/kg 300mg C

3 5

2.64/9.34d 23.2/705 d •e

a b c d e

Range of mean concentrations in serial lavages only. 'Ultravent' nebuliser, using a compressed airflow and inhalation of 4 mg/kg over 30 to 45 minutes for up to 15 days. 'Respirgard II' nebuliser, using compressed oxygen to deliver a 300mg dose of pentamidine over 35 to 40 minutes. Mean concentrations in bronchoalveolar lavage supernatant/sediment. Both supernatant and sediment concentrations were significantly higher after inhaled administration (p < 0.05).

breathing patients with values attained in a group on mechanical ventilation (because of respiratory failure) following inhalation of a 4 mg/kg dose over 20 to 40 minutes from an ultrasonic nebuliser. Pentamidine was undetectable in plasma from 5 of the 18 patients breathing spontaneously and the mean peak concentration was 66 J,tg/L in the remainder. In contrast, the mean peak concentration was 3.3-fold greater (216 J,tg/L) in the 8 patients undergoing mechanical ventilation. Herer et al. (1989) have reported a plasma concentration of 15 J,tg/L 35 days after the last dose of an 18-day treatment schedule with pentamidine (mesylate) 4 mg/ kg/day by aerosol in 1 patient. Conte and Golden (1988) measured plasma concentrations after inhalation of pentamidine 4 mg/kg/day for 1 to 18 days in patients with PCP. The results are presented in table I and clearly show the very limited absorption after inhalation. No pentamidine was detectable between 2 and 24 hours after inhalation. Bronchoalveolar concentrations of pentamidine after inhalation are substantially greater than after intravenous administration (table II).

2.2.2 Deposition in the Lungs In 1988 O'Doherty and colleagues measured the central versus peripheral lung deposition of pentamidine from 4 different aerosols in 9 AIDS

patients with PCP. The patients received single doses of pentamidine 50 or 300mg with 99Tc-labelle9 human serum albumin. Dynamic imaging. (during inhalation) revealed the most rapid deposition with 'System 22 Mizer', followed by 'System 22' and 'Pulmosonic', and then 'Respirgard II', while static imaging (after inhalation) also revealed the greatest deposition with 'System 22 Mizer'. The 'Respirgard II' system produced the most uniform distribution of drug throughout the lung and the least individual variation. This study did not measure particle size. However, the valve between the nebuliser and mouthpiece in the 'Respirgard II' system reduces particle size and therefore improves distribution of pentamidine in the lung (O'Doherty et al. 1988; Simonds et al. 1989a). The 'System 22 Mizer' includes a storage chamber between the patient and the nebuliser· to conserve aerosol during exhalation and improve efficiency (O'Doherty et al. 1988), but the increased particle size produced by this aerosol may result in less alveolar deposition and a greater risk of largeairway-related adverse effects (Simonds et al. 1989a) [see section 4]. Abd et al. (1988), using a similar radiolabel technique, found less efficient deposition of pentamidine in the upper lung of a 46-year-old man with AIDS from an ultrasonic nebuliser (probably 'Pulmosonic') producing a mass median aerodynamic diameter (MMAD; see section 2.3) of 2.9J,tm

746

than from a jet nebuliser rUltravent') with an MMAD of 0.7/Lm. The patient inhaled a mixture of pentamidine and 99Tc-DTPA, charged with 50mCi (about ImCi delivered). The greater central airways impaction with the larger particles may have accounted for the poorer drug penetration and failure of the ultrasonic nebuliser to prevent bilateral upper lobe infiltration in this patient who received pentamidine 300mg weekly for 6 weeks. There have been other cases of the development of localised or atypical pulmonary manifestations of P. carinii in patients receiving prophylactic therapy with inhaled pentamidine (Blumenfeld et al. 1988; Bradburne et al. 1989; Conces et al. 1989; Lowery et al. 1988; Scannell 1988). The relationship with pentamidine administration is unclear, although uneven pulmonary distribution of inhaled pentamidine may be a factor to consider (see also section 4). Simonds et al. (1989a) measured whole lung retention of radiolabel 24 hours after administration of 99mTc-Sn-colloid-labelled pentamidine (considered to reflect alveolar deposition only) and compared alveolar deposition from 3 different aerosols in 9 AIDS patients requiring secondary prophylaxis against PCP. There was 73% retention with 'Respirgard II ', 53% with 'Respirgard II' without the baffle and 47% with 'System 22' (see table III for details of formulations). Thus, alveolar deposition would appear to be inversely correlated with particle size, although this assumes that the deposition of pentamidine and Tc-Sn-colloid-labelled pentamidine are equivalent. Subsequently these authors have compared the pulmonary delivery of pentamidine from the 'Respirgard II' nebuliser with that from a modified 'System 22' nebuliser, incorporating an inspiratory baffle at the outlet of the nebuliser chamber and a filter at the expiratory limb of the circuit (Simonds et al. I 989b). Six patients with AIDS and stable respiratory function were included in the single-blind, crossover study, and received l50mg doses of 99Tc-human serum albumin-labelled pentamidine. MMAD was equivalent with each nebuliser (0.95/Lm with the modified 'System 22' and 1.0/Lm with 'Respirgard II'), as was the alveolar deposition fraction (0.54 vs 0.49, re-

Drugs 39 (5) 1990

spectively). The total dose delivered was low with both nebulisers, but was greater with the modified 'System 22' (1.17% of the initial dose) than with 'Respirgard II' (0.72%). 2.3 Aerosol Formulations and Particle Size Pentamidine has been employed in a range of different aerosol formulations. Broadly these can be divided into jet nebulisers, driven by compressed air or oxygen and ultrasonic nebulisers in which a piezoelectric crystal generates an ultra-high frequency sound which in turn generates a geyser action distributing particles (Newman et al. 1987). These different formulations create particles of different sizes according to: the pressure of gas or frequency of sound used and whether filters/baffles or reservoirs are included. Jet nebulisers involve a continuous delivery of aerosol while some ultrasonic nebulisers deliver drug only during inhalation and may therefore be more efficient. In one study ultrasonic nebulisers produced only a very small percentage of small particles « 2/Lm) compared with jet nebulisers, and had a very high interindividual variation in total drug output (Newman et al. 1987). Larger particles rarely reach beyond the central airways, but as a result of Brownian motion small particles « 0.5/Lm) deposit randomly throughout the lung (Corkery et al. 1988). The optimal particle size for alveolar deposition is considered to be I to 2/Lm (Corkery et al. 1988; Simonds et al. 1989a, b) while that for tracheobronchial deposition is 4 to 7/Lm (Corkery et al. 1988). Armstrong and Bernard (1988) reported good distribution of 99Tc-Iabelled pentamidine in the lung with an ultrasonic nebuliser delivering 2 to 5/Lm particles, although whether they measured alveolar deposition is unclear. Table III shows the MMAD and geometric standard deviation (GSD) of particles produced by some of the aerosols discussed in this review. MMAD reflects the median particle size and is measured using a laser-diffraction particle sizer or a cascade impactor. Because of the different techniques and procedures used, direct comparisons of

Inhaled Pentamidine: A Review

747

Table III. Particle sizes produced by some aerosol formulations used. with pentamidine Type of aerosol

MMAD (I'm)

GSD

Ultrasonic; no filter; reservoir

2.9 a

3.3

Jet; filter; no reservoir

0.7 a

2.2

Reference

Product

Abd et al. (1988)

'Pulmosonic' 'Ultravent'

1.3b 0.8 b

Godfrey-Faussett

'System 22'

Jet; no filter; no reservoir

et al. (1988)

'System 22+'

Jet; filter added

Miller et al.

'System 22'

Jet; no filter; no reservoir

2.6 b

2.9

(1989)

'Respirgard II'

Jet; baffle valve; reservoir

0.8 b

1.5 1.9

Montgomery et al. (1988)

'Respirgard II'

Jet; baffle valve; reservoir

1.4a

Simonds et al.

'Respirgard II'

Jet; baffle valve; reservoir

(1989a)

'Respirgard II'

Jet; baffle removed; reservoir

1.0b 1.7 b

'System 22'

Jet; no filter; no reservoir

3.4 b

a b

Measured using a cascade impactor. Measured using a laser diffraction particle sizer or laser droplet analyser.

Abbreviations: MMAD

= mass median

aerodynamic diameter; GSD

= geometric standard deviation (MMAD divided by

particle size

at the 84th percentile of the total mass).

values between studies should not be made. However, Godfrey-Faussett et al. (1988) clearly show how a filter can reduce the particle size, while other studies show a similar benefit with a one-way baffle valve (Miller et al. 1989; Montgomery et al. 1988; Simonds et al. I 989a).

Hauptman 1988). Conventional therapy is with cotrimoxazole (trimethoprim-sulfamethoxazole) or parenteral pentamidine, but such therapy is associated with a significant failure rate and, more importantly, a high degree of toxicity. Inhaled pentamidine offers the possibility of an effective

Current evidence suggests that particle size is

treatment for PCP in AIDS patients without the

the single most important factor in determining adequate distribution of pentamidine within the lung. The con~entration of drug deposited in the larger airways will depend on particle size and efficiency of the nebuliser. In view of this, well controlled trials comparing the particle sizes and lung deposition of pentamidine from the available aerosol formulations would be of value. Effective PCP prophylaxis has been reported with less efficient nebulisers producing small particles (e.g. 'Respirgard II') and more efficient nebulisers producing larger particles (e.g. ultrasonic nebulisers such as 'Fisoneb') [see section 3.2].

problem of systemic toxicity. In addition, this reduced risk of toxicity enables the drug to be studied as prophylaxis for the prevention of primary or recurrent disease.

3. Therapeutic Trials

3.1 Treatment of PCP Table IV summarises the studies reported to date of the therapeutic use of pentamidine aerosols in AIDS patients with PCP. These studies generally included patients with a first episode of mild PCP. Treatment outcome was assessed according to clinical symptoms, chest x-ray and pa02. Miller et al. (1989) originally employed the 'System 22' nebuliser in 14 patients, with poor results. Subsequently they repeated their study in 16 patients us-

Over 60% of patients with AIDS develop PCP at some stage, and the rate of recurrence of this infection in such patients has been reported in the range 30 to 85% (Conte et al. 1987; Wordell &

ing the 'Respirgard II' nebuliser and achieved much more encouraging results (81 % response rate), consistent with the findings of other investigators who have shown initial response rates in the range 68

Drugs 39 (5) 1990

748

to 100% with this preparation (see table IV). The few small studies employing ultrasonic nebulisers have shown initial response rates of about 50 to 70%. Comparison of the results between studies is difficult because different aerosol formulations were used (the actual dose and particle size of pentamidine delivered is often unclear) and there are no objective means of comparing the condition of patients at baseline. Recently, Simonds et al. (1989a) showed the 'System 22' aerosol to produce poor alveolar deposition of pentamidine (see section 2.2.2) and this may account for the poor therapeutic result seen using this formulation (GodfreyFaussett et al. 1988). The high response rate achieved with 'Respirgard II' also correlates with the findings of Simonds et al. (1989a). In general, where treatment was successful, cure occurred in 2 to 3 weeks. There were 3 early recurrences of PCP among the 9 patients treated successfully with inhaled pentamidine by Conte et al. (1987), but the other 6 patients remained free from symptoms during follow-up (for I to 9 months). Moreover, after I year of follow-up in the Montgomery et al. (1987) study there had been only 2 recurrences among the 13 successfully treated patients (Corkery et al. 1988). Miller et al. (1989) noted no PCP recurrence during follow-up for up to 20 months in any of their 16 successfully treated patients, although 3 died from other causes. These patients were receiving prophylactic regimens of oral cotrimoxazole and zidovudine (azidothymidine) [n = 11) or inhaled pentamidine (n = 3). In marked contrast, Conte et al. (1989) reported relapse within 3 months in 10 of 15 patients successfully treated with inhaled pentamidine. The explanation for this particularly high relapse rate is unclear. Montgomery et al. (1987) carried out a retrospective comparison of their results using inhaled pentamidine with the results obtained with alternative treatments in other studies at the same hospital, in patients with first episodes of PCP. Successful treatment not requiring a change in therapy was achieved in 13/15 patients (86%) on inhaled pentamidine, 13/15 patients (86%) on trimethoprim-dapsone, 8/20 patients (40%) on parenteral

pentamidine and 5/20 patients (20%) on co-trimoxazole. Conte et al. (1987) showed equivalent response rates with inhaled and intravenous pentamidine (see table IV). The AIDS Clinical Trials Group in the USA are currently undertaking a well-controlled trial comparing the therapeutic efficacies of co-trimoxazole and inhaled pentamidine (,Respirgard II') in AIDS patients with PCP. The intention is to include 240 patients via about 24 centres, and treatment would continue for 21 days with a further 6 months' follow-up. An interim analysis of the first 205 patients revealed PCP recurrence in 8 of 136 patients followed for I to 3 months, and 6 of 74(8.1 %) followed for 4 to 6 months (Montgomery et al. 1989b). 3.2 Prophylaxis of PCP The first aerosol prophylaxis studies were reported by Bernard et al. (1987, 1988b). A handheld ultrasonic nebuliser (Siemens) was used (mean particle size 5,um) to deliver doses of pentamidine of 30mg every 2 weeks in 60 AIDS patients, 45mg weekly for 4 weeks then every 2 weeks in 84 patients and 60mg weekly for 4 weeks then every 2 weeks in 115 patients. The mean duration of follow-up was 3.2, 3.9and 5.1 months, respectively, and the number of PCP cases recorded per 100 patient months was 4.1, 3.0 and 1.5, respectively (Bernard et al. 1988b). In the absence of any control group it is difficult to draw any constructive conclusions from these results. Subsequently, a number of significant prophylaxis studies have been reported with inhaled pentamidine isethionate. Table V presents some key details and the primary results of these studies; some were uncontrolled with data collected retrospectively, others, in particular the Canadian Cooperative Trial and the San Francisco trial, were prospective comparative studies. The patients included had AIDS or AIDS-related complex (ARC) and were at risk of developing PCP; most patients had experienced at least 1 previous episode of PCP. The maintenance dosage of pentamidine used

749

Inhaled Pentamidine: A Review

Table IV. Outcome of treatment with inhaled pentamidine in AIDS patients with PCP

Reference

Conte et al. (1987)

Conte et al. (1989)

Treatment and dosage

'Ultravent' 4 mg/kg/day over 30-60 min for 1-15 days IV administration 3 mg/kg/day; 2-hour infusion for 9-18 days 'Respirgard 11' 600mg daily IV administration 3 mg/kg/day

No. patients with primary/recurrent PCP

Treatment outcome effective

ineffective and/or not not tolerated evaluable

9/4

9a

3b

7/2

8e

0

23 22

17d 17d

4 4

2

15

9

5

1 0

15

12

3

5

3

Dellamonica et al. (1989)

Ultrasonic nebuliser, 600mg daily as mesylate salt for 21 days IV trimethoprim/sulphamethoxazole 20/100 mg/kg/day for 21 days

Girard et al. (1988a)

'Ultraneb 99' 4 mg/kg/day over 30-75 min for 1-21 dayse

Girard et al. (1989b)

'Respirgard 11' 300mg daily for 7-21 days

43/209

43

20

Girard et al. (1990)

'Respirgard' jet nebuliser 300 mg/day for 21 days 'Respirgard' jet nebuliser 600 mg/day for 21 days

117

56

28

33

103

49

23

31

Meyer & Dietrich (1989)

'Respirgard 11' 300mg daily for 21 days

28

19 h

9

0

Miller et al. (1989)

'System 22' 4 or 8 mg/kg/day over 15-30 min for 2-15 days 'Respirgard 11' 8 mg/kg/day over 15-30 min for 6-19 days

14

3

10

Ii

16

13

3

0

Montgomery et al. (1987)

'Respirgard II' 300mg daily over 20 min for 21 days

15/0

13

2

0

Montgomery et al. (1989a)

'Respirgard 11' 600mg daily over 25 min for 5-17 days

5/5

10

0

0

a b c d e f g h

8/2

2'

Three patients had an early recurrence of PCP. Early discontinuation in the first 3 days of treatment. Two of these early successes had to change therapy after 10 and 11 days because of intolerance to IV pentamidine. Early relapse (within 3 months) occurred in 10 patients in the 'Respirgard II' group vs 0 in the IV group (p < 0.05). This study employed pentamidine mesylate and an ultrasonic nebuliser delivering particles with an MMAD of 4,6jLm. One patient improved but was lost to follow-up, the other remained febrile but also developed disseminated infections. Interim report of a study intending to include 120 patients. Including 1 patient whose chest x-ray was not completely cleared and 1 patient who subsequently relapsed. One patient died from massive haemorrhage after transbronchial biopsy.

Drugs 39 (5) 1990

750

Table V. Prophylaxis with inhaled pentamidine in AIDS or ARC patients at risk of developing PCP

Reference

Treatment and dosage

No. of No. of patients Mean with;;' 2 past follow-up patients evaluated PCP episodes time (months)

Bernard et al. (1989)

'Fisoneb'a 60mg once weekly for 4

266

weeks then bimonthly

Canadian Cooperative Trial b

'Fisoneb' 60mg bimonthly Placebo

Fallat et al. (1988)

Baffled nebuliser, mean 36mg bimonthly

Girard et al. X1989a)

'Ultraneb 99'c 4 mg/kg pentamidine mesylate bimonthly for 1 month then monthly + zidovudine 200mg every 4 hours Zidovudine 200mg every 4 hours alone

84 78

9.6

25

9.4

3.7

5 27

5.9 34.6

33

5

17

8.5

22

3

10

2

9.1

26

0

8.7

16

61 .5

5.5

10

8.5

6.4

10

10.7 3.1

'Ultraneb 99'c 4 mg/kg pentamidine mesylate bimonthly for 1 month then monthly

129

Golden et al. (1989)

'Ultravent' 300mg monthly

103

12

97

l1d

3

58

6

9

'Respirgard II ' 30mg bimonthly 'Respirgard II' 150mg bimonthly 'Respirgard II' 300mg monthly

1171 1201 1291

10

22 16 8

'Acorn System 22' 300mg fortnightly Trimethoprim 160mg + sulfamethoxazole 800mg twice dailyh

17 16

'Pulmosonic' 60mg every 3 weeks

Recurrence rate (%)

211

Girard et al. (1988b)

Keyes et al. (1989)

63

No. of recurrences

administered to supine patient Samuels et al. (1989) San Francisco tria

,e

Sriiith et al. (1990)

'Pulmosonic' 60mg weekly for 4 weeks then bimonthly

Staszewski et al. (1990) 'Respirgard II' 200 mg/day forA days, then fortnightly + zidovudine

120i

;;. 69

24

16 18.8 13.3 6.2 6 6

9.4

7

6

Torres et al. (1989)

'Pulmosonic' 100mg bimonthly Dapsone 100mg biweekly

65 53

6 5

6 3

9 6

Van Gundy et al. (1988)

Jet nebuliser 2 mg/day bimonthly + zidovudine

29

6

4

13.8

a b c d e f

9 h

'Fisoneb ' is an ultrasonic nebuliser with a reservoir but no filter system, and a predicted MMAD of 5/Lm (Corkery et al. 1988). Data from Montaner et al. (1989). 'Ultraneb' is an ultrasonic nebuliser producing an MMAD of 4.6/Lm and GSD of 1.9/Lm . Median value. Data from Corkery et al. (1988) and Leoung et al. (1988, 1989a). This analysis is based on eligible patients with confirmed PCP only, of the 408 patients enrolled in the study. Total follow-up time. 75% of all patients concurrently receiving zidovudine. 80 patients primarly, 40 secondary prophylaxis.

Inhaled Pentamidine: A Review

ranged from a mean of 60mg per month to 300mg per month. Recurrence occurred in 6 to 16% of patients receiving ~ 120mg pentamidine monthly in these studies over mean periods of 4 to 10 months, and was generally mild and responsive to treatment. No studies have compared the use of different nebulisers, so it is impossible to determine whether any particular preparation provides a therapeutic advantage. The studies can broadly be divided into those using lower dosages (usually 60mg every 2 weeks) and those using higher dosages (300mg monthly), but a variety of different preparations have been employed in each category and the PCP recurrence rates - ranging from 5.9 to 16% with 120mg monthly and 6.2 to 13.3% with 300mg monthly - cannot be distinguished according to dosage. The San Francisco dose-comparison study enrolled 408 HIV-positive patients, including among the evaluated patients 237 who had previously experienced PCP, 55 with Kaposi's sarcoma and 116 with AIDS-related complex. 67 physicians from 12 clinical centres randomly allocated patients to one of the three inhaled pentamidine treatment groups (see table V) [Corkery et at. 1988; Leoung et at. 1988, 1989a]. About half the patients were also receiving zidovudine and the risk of PCP occurrence was about 3 times lower in these patients than in those not receiving zidovudine. The risk of developing PCP over the 18-month follow-up period was significantly reduced (p < 0.01) with a dosage of 300mg monthly compared with 30mg bimonthly, administered via the 'Respirgard II' system in each case (see table V), and this difference was not influenced by the use of zidovudine. A preliminary analysis had revealed relapse in 6/152 patients (3.9%) with I previous PCP episode compared with 37/152 historical case controls (24.3%) matched for time since previous episode, a reduction in relapse rate of 84% (Leoung et al. 1988). In the double-blind Canadian Cooperative Trial, patients were randomly allocated to prophylaxis with inhaled pentamidine 60mg every 2 weeks (via 'Fisoneb') or placebo for 6 months, 2 to 24 weeks after a first episode of AIDS-related PCP. The re-

751

currence rate was reduced by 83% in the pentamidine group (see table V), which was highly significant (p < 0.0001). A similar percentage reduction (85%) was reported in a smaller, controlled study comparing pentamidine mesylate (4 mg/kg monthly via 'Ultraneb 99') plus zidovudine with zidovudine alone in 48 AIDS patients who had experienced an episode of PCP within the last 5 months (Girard et al. 1989a; see table V). However, there was no difference in the survival rates in the 2 groups after the mean follow-up period of 9 to 10 months: 68% in the pentamidine group versus 60% in the zidovudine alone group. Torres et al. (1989) found a similar relapse rate among patients with AIDS or severe AIDS-related complex randomised to treatment with inhaled pentamidine or self-administered oral dapsone (see table V). 60% of the 118 evaluable patients were receiving zidovudine, equally divided between the treatment groups, and the relapse rates in this subgroup were higher than in patients not receiving zidovudine (13% on pentamidine and 10% on dapsone versus 9% and 6%, respectively). Other studies have shown similar or slightly higher PCP recurrence rates in patients receiving concurrent zidovudine compared with those receiving inhaled pentamidine alone (Golden et al. 1989; Rodriguez et al. 1989). The risk of PCP recurrence was considerably greater in patients who had experienced at least I previous episode than in patients who had never had a previous episode. Other, uncontrolled studies compared the recurrence of PCP, in patients who had experienced I previous episode, between the prophylactic inhaled pentamidine group and a matched group of historical controls who had not received such prophylaxis. In 2 studies the incidence of PCP in the pentamidine group was reduced by 50% and over 67%, with the pneumonia-free period being prolonged by about 6 months (Fallat et al. 1988; Feigal et al. 1988; Golden et al. 1989). In a third study the incidence of recurrence per 100 patient months was 0 in the pentamidine group versus 6.7 in the control group (Bernard et al. 1988a). Staszewski et al. (1990) found pentamidine to

752

be effective in both primary and secondary prophylaxis, the incidence of PCP being reduced by 75% in patients receiving pentamidine and zidovudine in comparison with a group of historical controls receiving zidovidine alone.

4. Adverse Effects With parenteral administration of pentamidine toxicity is common, occurring in about 50% of patients. The most frequently reported problems are nephrotoxicity, hypoglycaemia, hypotension, leucopenia, thrombocytopenia and hepatic dysfunction (Goa & Campoli-Richards 1987; Wispelwey & Pearson 1990). Among 164 patients treated with pentamidine in New York hospitals during a IO-month period in 1984, 94 experienced some form of toxicity (57.3%), including azotaemia in 23%, hypotension in 14% and hypoglycaemia in 14% (Waskin et al. 1988). With inhalation of pentamidine the incidence of toxicity is markedly different. In clinical trials there have generally been no reports of treatment-related systemic side effects. Indeed, Armstrong and Bernard (1988) observed no serious adverse reactions or long term toxicity with inhaled pentamidine prophylaxis in over 3 years of study. Their trials included about 450 schedules of pentamidine prophylaxis with dosages of 30 to 60mg every 2 weeks in AIDS patients (Bernard et al. 1988a,b). Conte et al. (1987) reported neutropenia in 2 patients and a minor rash in I among 10 patients receiving inhaled pentamidine 4 mg/kg/day, but both of the former had low pretreatment leucocyte counts and were receiving zidovudine concurrently. Although systemic adverse effects are rare with inhaled pentamidine, there have been isolated reports of toxicity, demanding that careful observations be made particularly in patients who have developed serious adverse effects on parenterally administered pentamidine. There has bee.n only I report of a low fasting blood glucose concentration (~ 70 mg/dl; ~ 3.9 mmol/L) in a patient receiving inhaled pentamidine 300mg, and this was of questionable relationship to treatment (Karboski & Godley 1988). Moreover, Havlichek (1988) found

Drugs 39 (5) 1990

no evidence of hypoglycaemia with inhaled pentamidine 300 to 600mg daily in a patient who had developed hypoglycaemia previously on parenteral pentamidine. Other serious adverse effects reported with inhaled pentamidine have included: maculopapular rash in 2 patients, after 17 weeks' treatment on 600mg weekly (Leen & Mandai 1988) and 1 year on 60mg twice monthly (Berger et al. 1989), respectively; pancreatitis in 2 patients after therapy with pentamidine mesylate 4 mg/kg/day (Herer et al. 1989) and in 1 after long term prophylaxis with pentamidine 60mg twice monthly (Hart 1989). In all studies cough and bronchospasm associated with inhalation have been common and have occasionally required treatment discontinuation. Such respiratory adverse effects would seem to occur more frequently with aerosol formulations which deliver larger particles (O'Doherty et al. 1988; Simonds et al. 1989a,b), although the higher incidence could also be related to the greater dose of drug delivered by more efficient nebulisers. Smith et al. (1988) demonstrated a 75% reduction in peak expiratory flow rate (PEFR) in 8 patients receiving pentamidine 300mg (,System 22' nebuliser) prophylactically every 2 weeks for PCP. The next 52 patients treated by this group received pretreatment with salbutamol 5mg, with the result that PEFR declined only 1.2% after pentamidine inhalation. This finding is supported by several case reports in which pretreatment with inhaled terbutaline (Jesuthasan et al. 1987) or ipratropium (Heley 1987) overcame problems of pentamidine-induced bronchospasm. Some authors recommend routine bronchodilator pretreatment in patients receiving inhaled pentamidine; such advice would seem prudent in asthmatic patients. Coughing may be controlled by slowing the delivery or intensity of the aerosol stream (Armstrong & Bernard 1988). The sulphonate moiety of pentamidine isethionate may account for the irritation and cough induced in many patients, or pentamidine may have a direct action on the bronchioles (Martinez et al. 1988). In 6 AIDS patients with a history of inhaled pentamidine prophylaxis, the development of pneumothoraces may have resulted from this ir-

Inhaled Pentamidine: A Review

ritation and coughing (Martinez et al. 1988). Miller and Semple (1988) recorded severe contact bleeding (and haemoptysis in I case) during bronchoscopy in 5 of 16 patients who received pentamidine 8 mg/kg/day for I to 6 days ('Respirgard II' nebuliser). They attributed this to bronchial irritation induced by the low pH (5.4) of the administered pentamidine solution. In the San Francisco prophylaxis trial there were 13 episodes of pneumothorax among the 408 patients receiving inhaled pentamidine for a mean period of 301 9ays. There was no dose relationship, 2 episodes were associated with invasive procedures, and the authors concluded that the penumothoraces were more likely associated with PCP per se than with inhaled pentamidine (Leoung et al. 1989b). Supporting this conclusion is the result of a retrospective study of the incidence of pneumothorax in patients receiving inhaled ('Respirgard II' 100mg every 2 weeks) or intravenous (4 mg/kg/monthly) pentamidine (Newsome et al. 1989). Prophylaxis was continued for 3 to 13 months. Pneumothoraces occurred in 8/327 patients (2.4%) on inhaled pentamidine versus 0/35 patients on intravenous pentamidine (not statistically different) and most occurrences were associated with active PCP and/or cystic lung disease. There are reports of patients developing isolated P. carinii infections in the upper lung zones during prophylaxis with inhaled pentamidine 150mg monthly or every 2 weeks (Bradburne et al. 1989; Conces et al. 1989). Furthermore, Lowery et al. (1988) compared the pattern of PCP in patients before inhaled pentamidine therapy and those with relapse after pentamidine therapy. There was a diffuse pattern of infection in the lungs in all 26 of the former patients, but infiltration was only in the upper lobes, or predominantly so, in 15 of 24 of the latter. These infections may be related to nonuniform distribution of pentamidine in the lungs as a result of suboptimal particle sizes (see section 2.2.2) or inadequate total doses administered. There are also rare reports of extrapulmonary pneumocystosis occurring in patients receiving inhaled pentamidine prophylaxis. A 33-year-old man developed P. carinii apical pneumonitis and pneu-

753

mothoraces complicated further by P. carinii hepatitis while being treated prophylactically with inhaled pentamidine (Poblete et al. 1989). Widely disseminated pneumocystis infection resulting in death has been reported in 2 patients who had been receiving prophylaxis with inhaled pentamidine (Davey et al. 1989; Ward 1989). An analysis of 10 patients who developed extra pulmonary pneumocystosis while receiving inhaled pentamidine prophylaxis revealed several features in common. Infection was widely disseminated and often without concurrent pneumonia. AIDS had been diagnosed at least I year previously and inhaled pentamidine prophylaxis had been ongoing for at least 7 months, with concurrent administration of zidovudine in the majority of patients (Northfelt 1989). It has been suggested that such extra pulmonary infections may become more common as inhaled therapy becomes more widespread at the expense of systemic suppression (Davey et al. 1989; Ward 1989). In an ongoing study of the treatment of PCP in AIDS patients with inhaled pentamidine, undertaken by the AIDS Clinical Trials Group, there have been no cases of pulmonary haemorrhage or extrapulmonary pneumocystosis among the 205 patients enrolled (Montgomery et al. 1989b).

5. Dosage and Administration For the prevention of PCP in high-risk human immunodeficiency virus (HIV)-positive patients (i.e. those who have had at least I previous episode of PCP or have a T 4 cell count of ~ 200/mm 3) the recommended dosage of inhaled pentamidine employing a jet nebuliser delivering particles of small size (e.g. 'Respirgard II') is a single 300mg dose every 4 weeks. However, several different aerosols have been employed in clinical trials and dosages of 60mg every 2 weeks, delivered via more efficient ultrasonic nebulisers producing particles of a larger average size, also appear effective. The type of inhaler used seems crucial in determining the success or failure of prophylaxis. Advantages and disadvantages have been proposed for the various jet and ultrasonic nebulisers available, according to their efficiency in delivering drug to

Drugs 39 (5) 1990

754

the lungs and the particle size produced (see section 2.3). However, there have been no controlled trials comparing the effectiveness of any of these formulations. With jet nebulisers it is important that there is consistent and accurate regulation of flow and pressure; a flow rate of about 6 L/ min is recommended (Corkery et al. 1988) and has been most widely employed. For the treatment of PCP pentamidine 300 or 600mg daily inhaled over 15 to 30 minutes via the 'Respirgard II' system, and continued for an average of about 15 days has proved effective in patients with mild disease. However, it is doubtful at this time whether such therapy should replace the established treatment (see section 6).

6. Place of Inhaled Pentamidine in the Management of pCP In view of the high level of toxicity associated with cotrimoxazole and parenteral pentamidine in the treatment of PCP, and the frequency and severity of relapse of PCP in AIDS patients, there is a need for a safer alternative both for the treatment and prophylaxis of the disease. Inhaled pentamidine certainly offers a far superior toxicity profile to standard therapy or prophylaxis, with virtually no systemic effects and respiratory symptoms readily controllable in most patients in whom they occur. The number of AIDS patients with established PCP trea ted with inhaled pentamidine in clinical trials is relatively small (about 200). These patients have had only mild disease and yet treatment failure has occurred in some. Comparison of the results with those in historical control groups receiving standard therapies seems encouraging. However, until the results of well controlled studies are reported the place in therapy of inhaled pentamidine monotherapy for PCP remains unclear; possibly it may prove useful as an adjunct to parenteral therapy in some patients, but again this requires clinical investigation. Because of its good tolerability profile inhaled pentamidine offers a logical choice for prophylaxis

in patients at high risk of developing PCP. Clinical trials in this area have been more extensive and have revealed very encouraging results in prospective comparative studies and in comparison with matched historical control groups. Several aerosol formulations delivering different particle sizes and different dosages have been shown to be effective, but there have been no controlled studies comparing the different formulations to establish clinical advantages, if any. However, the results obtained thus far in AIDs patients at high risk of developing PCP indicate that routine prophylaxis with inhaled pentamidine may become the accepted treatment of this potentially lethal disorder.

References Abd AG, Nierman DM. 1I0wite JS, Pierson RN, Bell ALL. Bilate ral upper lobe 1'1I(,lI l11oCl'slis Cf1l'illii pneumonia in a patient receivi ng inhaled pentamidine prophylaxis. Chest 94: 329-331. 1988 Armstrong D, Bernard E. Aerosol pentamidine. An nals of Inlernal Medicine 109: 852-8 53, 1988 Arnoll MA, Hay J , Croft SL. Pentamidine: which sail" Lancet I: 1057-1058, 1988 Barticll HS, EichhOltz R, Miller J, Smith JW. Activily of antimicrobial agents again st 1'1ll'1I1110(I'Slis Cf1l'illii (PC) in cu llure. Abstract no. 496, 23rd Meeting of the ICAAC Las Vegas, Oclober 24-26, 1983 Belehu A, Naafs B. Diabetes mellitus associaled wilh pentamidine mesylate. La ncet I: 1463-1464, 1982 Berger TG , Tappero JW, Leoung GS, Jacobso n MA. Aerosolized pentamidine a nd cu ta neous eruptions. An nals of Internal Medicine 11 0: 1035- 1036. 1989 Bernard EM, Dickmeyer MS, Schmill H, Armstrong D. Long term safety and effecti veness of aerosol pentamidine for prevention of PI1 l'1I1110