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Pentam (Pentamidine Isethionate) - Description and Clinical Pharmacology

 
 



For Injection Only

DESCRIPTION

Pentam 300 (pentamidine isethionate for injection), an anti-protozoal agent, is a sterile, nonpyrogenic, lyophilized product.  After reconstitution, it should be administered by intramuscular (IM) or intravenous (IV) routes (see DOSAGE AND ADMINISTRATION ).  Pentamidine isethionate is a white crystalline powder soluble in water and glycerin, slightly soluble in alcohol and insoluble in ether, acetone, and chloroform.  It is chemically designated as 4,4-[1,5-pentanediylbis(oxy)]bis-benzenecarboximidamid with the following structural formula:

 

Each vial contains:
Pentamidine isethionate. .. .. .. .. .. .. 300 mg

CLINICAL PHARMACOLOGY

Pentamidine isethionate, an aromatic diamidine, is known to have activity against Pneumocystis carinii .  The mode of action of pentamidine is not fully understood.  In vitro studies indicate that the drug interferes with protozoal nuclear metabolism by inhibition of DNA, RNA, phospholipid and protein synthesis.

Pharmacokinetics

Pharmacokinetic parameters following the administration of 4 mg/kg pentamidine isethionate as a single two-hour intravenous infusion or after a single intramuscular injection to 12 patients with AIDS are presented in the following table:

Mean ±

SD

Cmax

ng/mL

Clearance

L/h

Half-life

hours

Vdss

L

Concentration

ng/mL

8 hour

24 hour

2 hour I.V. infusion

4 mg/kg (N=6)

612 ± 371

248 ± 91

6.4 ± 1.3

821 ± 535

19.3 ± 16.9

2.9 ± 1.4

I.M.

4 mg/kg (N=6)

209 ± 48

305 ± 81

9.4 ± 2.0

2724 ± 1066

22.9 ± 8.0

6.6 ± 3.5

In seven patients treated with daily IM doses of pentamidine at 4 mg/kg for 10 to 12 days, plasma concentrations were between 300 to 500 ng/mL.  The concentrations did not appreciably change with time after injection or from day to day.  Higher plasma concentrations were encountered in patients with an elevated blood urea nitrogen.  The patients continued to excrete decreasing amounts of pentamidine in urine up to 6 to 8 weeks after cessation of the treatment.

Following multiple intravenous administration of pentamidine isethionate (3.7 to 4 mg/kg/day infused over 4 hours) to 6 patients with AIDS being treated for PCP, the pharmacokinetic parameters obtained on Days 1,4 and 7 are summarized in the following table:


Mean

 ± SD

Cmax*

ng/mL

Cmin*

ng/mL

Clearance

mL/min

Renal Clearance mL/min/1.73 m2

Creatinine Clearance mL/min/1.73 m2

Day 1

175.3 ± 54

---

5737 ± 1878

269 ± 149

97 ± 12

Day 4

210.9 ± 80

17.6 ± 9.5

3350 ± 1944

214 ± 145

93 ± 17

Day 7

256.7 ± 89

40.8 ± 16.1

1989 ± 566

134 ± 60

69 ± 17

*derived from Lidman

Compared to the mean AUC on Day 1, AUC on Day 4 and Day 7 were about 2 and 3 fold higher, respectively, suggesting that steady state was not achieved by Day 7 of dosing.

In other published reports of pharmacokinetics of pentamidine following daily intravenous doses of 2 to 4 mg/kg/day, clearance ranged from 30 to 40 mL/min/kg and Vdss ranged from 200 to 400 L/kg.  Reported values for terminal half-lives of 2.8 to 12 days is suggestive of a deep peripheral compartment.  In the urine, up to 12% of the administered dose has been recovered during a dosing interval as unchanged pentamidine.

Tissue distribution was studied in mice given a single intraperitoneal injection of pentamidine at 10 mg/kg.  The concentration was highest in the kidneys followed by the liver.  In mice, pentamidine was excreted unchanged, primarily via the kidneys with some elimination in the feces.  The ratio of amounts excreted in the urine and feces (4:1) was constant over the period of study.

Tissue distribution has also been studied in normal and in renally impaired dogs (N = 3 each) given 13 mg/kg of pentamidine IV, in 2 doses separated by five weeks.  The concentration of pentamidine was highest in the liver followed by kidneys and lungs.  Pentamidine was concentrated in these organs approximately 70 to 1000 times that of the peak serum concentration.  Similar findings were reported in normal and in renally impaired dogs (N = 2 each) given 97.5 mg/kg of pentamidine IV, in 15 daily doses.  After repeated doses, the organs showed a further 3 to 7 fold accumulation while serum concentrations remained unchanged.

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