DRUG DISPOSITION

(lin 1'h~r,"lcollnCI_ ~ O ( ~) : 99·113 . 1991 () 11 ~·j%l i 91 illOO1 ..00'I 2 months :z: 5.8 ± 1.2 hours]. T he pharmacokinctic profiles 3rc similar in CA PD patients. The prescnt authors found {hallhe mean serum cpoetin concent ration in 8 stable CA PO subjects given epoetin 120 U/kg intravenously deca yed monoexponentially from a peak o f 3959 ± 758 to 558 ± 181 U/ L at 24 hours. yielding a mean 1,It of 8.2 hours (range 6.2 to 10.2) and an el im inalion rate consta nt (kel) ofO.087/h (Macdougall et al. 1989d ). The mean Vd was 0.033 L/ kg (range 0.021 to 0.063 L/ kg) and the mean serum CL was 0.0028 L/ kg (range 0.00 1910 0.0051 L/kg). Losses of epeetin in the peritoneal dialysis fluid were found 10 be only 1.7 to 3.0% (mean 2.3%) of the total intravenous dose over the first 24 Ilours (Macdo ugall et al. I989d); tllus, the process of peritoneal dialysis itself did not result in significant epoetin clearance. These findings are supported by the similar plasma elimination half-li ves seen in this group compared with haemodialysis patients. Boelaert et al. (1989) obtai ned comparable results in a stud y o f 6CAPO patients in which a mean t'll of 11.2 ± 0.4 hours was found . The Vd was 5.0 ± 0.6% of the bodyweight. and CL was 0.0031 ± 0.0005 L/ h/ kg. Again, on ly 2.63 ± 0.45% of the intravenous dose adm inistered was eliminated in the peritoneal emuent over 24 hours, and for practical purposes this can be ignored. In summary, therefore, cumulative results from 15 studies involving 141 patients (table I) indicate a range of mean plasma t'll for epoetin of 4.0 to 11 .2 hours. which may shorten with repeated adm inistration. The Vd for this agent appears to be similar to plasma vol ume, and its CL is slower than for many other protein hormones, occurri ng predominantly via nomenal mechanisms. Thus, in

0111 . Pharmacok/lll'/ 10 (1) /991

comparison wi th insulin (2.88 L/ h/ kg: Katz & Rubenstei n 1973), glucagon ( 1.86 L/ h/ kg: Emmanouel et al. 1978) and prolactin (0.5 1 L / h/kg; Em manouel et al. 198 1). the metabolic clearance of erythropoictin in rats (0.016 L/ h/kg: Emmanouel et al. 1984) appears to be considerabl y slower. Glycoprotcin hormones, however, secm to share more prolonged circ ulatory survivals, as suggestcd by the sim ilarly slow clearance of homologous lutci nising hormone and follicle stimulating hormone (0.186 and 0.03 L/ h/ kg, respectively: Emmanouel et al. 1984). Whcthcr this is true in humans remains to be el ucidated. 3.2 Intraperitoneal In a tsud y in rabbits, Bargman and colleagues (1988) found that 60% of epoetin in dialysate (a nd 98% of thc drug injected into an empty peritoneal cavity) was absorbed, which suggestcd that cpoetin might be suita ble for intra peritoneal administration to paticnts on CA PO. Unfortunatel y, a number of studies subsequen tl y caTTied out in CAPD patients have failed to provide res ults which live up to that expectation (Boclaert et al. 1989; Gahl ct al. 1989; Hughes el al. 989; 1 Kampf et al. 1989; Macdougall et al. 1989d) (table 111. Epoetin concentrations becamc detectable in the circulation of CA PO patients after only I to 2 hours of an 8-hour dwell with a fixed int raperitoneal dose of 50 OOOU, rising to a peak (Cma ~) of 375 ± 123 U/ L at 12 hours, and falling slowly thereafter to 287 ± 135 U/ L at 24 h ours with a kcl ofO.032/h (Macdougall et al. 1989d). In another stud y, Kampfct al. (1989) achieved C mu ranging from 18 to 55 U/ L after an intraperito neal dose of 100 U/kg using a 12-hour dwell, and Gahl el al. ( 1989) observed a mean epoetin C mu of 52 ± 14 U/L using the same dose and dwell time. Using a shoner dwell period of 4 hours, Boelaen et al. (1989) obta ined a Cmu of 108 ± 18 U/L between 8 and 12 hours after an intraperitoneal dose of epoetin 300 U/ kg in their 6 CA PO patients. Prolongat ion of the dwell period to 12 hours in 3 patients increased the mean Cma~ to 170 ± 13 U/ L at 12 hours (Boelaen et al. 1989). Nevertheless, in all 4 studies the bioavailability of

'0'

Pharmacok'lletlcs of Epocun

Re'er8llC8

Paliefl,s

DoH (U{kg)

Boe'-ert ••• t (1989)

Gnl! •••1

6 CAPO 3 CAPO 9 C....PO

(li89)

Hughes III at (19119) Kampf a••1 ( .9119) Kromer a• • 1 (1990) MaCdOugall e. al ,,989(1)

3C .... PO 7 C.... PO 121PO

8 CAPO

300 300

H,. H,. H,.

Vol.'

'," , , ,

'"

.'

SOl''''

.5·2

,• , ,

VoI",me or dialySIs 1t",1(! G-24h ....ppro. ,ma •• vall,lll 56' 01 AUC alter 5ubculallll()US admllllstr,IIon

,

0 00 Dry per itoneal ~V1ty Tot., dose III "'llIIs

•,

AOCta~, .r,OtIS

F ,. bIoavallablllty.

....

C_. """ ''I (U/L)

•

106 or. 18

"" "

!: 13

52

!. 14

8 80 ml/ minJ. moderately impaired renal funclion (CLcR 10 to 50 ml/ min). and end-stage renal failure (CLcR < 3 ml/ min). respectively. Likewise. there was no cha nge in total body clearance between the J groups (0.0012 ± O.()(M)()J. 0.0051 ± 0.0004 and 0.()()48 ± 0.00 11 L/ h/ kg. res!)«tlvely). SImilarly. In 2 groups of health)' and uraemic (liveSixths nephrcctomised) rats. Scigalla et al. (1987) found no difference in either the plasma t,: (12.8 \'S 11.5 hours) or the renal clearances (0.0024 \·s 0.0030 L/ h/ kg) of biologically active J~ S-labellcd epoetin. again suggesting that the kidneys were not primarily involved In the melabohsm of epoetin.

Finally, Mladenovic and colleagues ( 1985) reported that the half-life of infused homologous erythropoietin-rich plasma in both normal and uraemiC sheep was approximately 9 hours. and was independent or renal function. the plasma clearanC(:s being 0.222 :t: 0.12 and 0.198 ± 0.108 L/h. res!)«tively. In contrast. a number of animal studies ha\'e suggested a role for the kidney in the metabolism of erythropoietin (Dinkelaar et al. 1981: Emmanouel et al. 1984: Fu et al. 1988: Naets & Wittek 1974: Spivak & Hogans 1989). Spivak and Hogans (1989) recen tly round that there was progressive accumulation of iodinated epoetin by the kidneys of anaesthetIsed rats compared wtlh other organs. and concluded that the kidney was involved to a small extent In the catabolism of the hormone. Furthermore. thIS was supported by their studies with desla1ated. oxidlscd epoetin. which also appeared to accumulate in the kidneys as opposed to other organs. In a pharmacok.inctic study in healthy and anephnc dogs. Fu 1.'1 al. (1988) found a slower

C/Irt. Pharmacoktnrt. 10 f1J 1991

lOS

-

....

Table III. Mlln ( :to SO) Of range 01 pharmacolu.... tlC parameters .tl8I' subCullneou. admnstrltlOn of epoetln

A,terente BoetMl1 II I' (1989) Olnielson (1988) Eorie I' ,I (1988)

'""""'/ patients 6 CAPO

(U{kg)

300

lUll)

I")

15 (2 PiS)

"'. "'. "'. .

10% 01 IV values

150(3 ptsl

Hughes II I' (1989)

9 CAPO

Kimple! II (1989)

5 PO/3 HO

Kromer a' ,I (1990)

12 fPO

MaCdOugall a' I I. (1989 131~

17 166

" "

:!:

~"

10.2 :1 'Il' 18.2 :1 2.1d

",

18 (23-250)

5218 (3 287·

", 49 (23