6 - I984 Pharmaceutisch Weekblad Scientific Edition. 229. REVIEW ARTICLES. Pharmacokinetic aspects during continuous ambulatory peritoneal dialysis:.
Vol. 6 - I984 Pharmaceutisch Weekblad Scientific Edition REVIEW
229
ARTICLES
Pharmacokinetic aspects during continuous ambulatory peritoneal dialysis: a literature review R. J A N K N E G T * w
AND
C . H . W . KOKS*
ABSTRACT
Since its introduction some years ago continuous ambulatory peritoneal dialysis (CAPD) has proved to be a valuable alternative to haemodialysis in the treatment of uraemia. Factors contributing to the transport of solutes through the peritoneal membrane are discussed and the literature concerning the pharmacokinetic aspects of CAPD is reviewed. (Pharm Weekbl [Sci] I984;6:229-36) INTRODUCTION Since its introduction in I977 continuous ambulatory peritoneal dialysis (CAPD) has proved to be a valuable alternative to haemodialysis and intermittent peritoneal dialysis in the treatment of uraemia. The increased mobility of the patient and the lower cost compared with haemodialysis have contributed to the established place CAPD has in the treatment of end stage renal disease. From the first report of CAPD I it has become clear that peritonitis was the most frequent complication of CAPD. Although usually benign it remains the leading cause of failure or death among CAPD patients. 24- Patients may have several episodes of peritonitis a year. Staphylococcus aureus and Staphylococcus epidermidis are the most frequent causative organisms, but Gram-negative rods of many different species may also be involved. 25 Because of the relatively high incidence of peritonitis (one episode in ten to twenty patient months), it is not surprising that antibiotics are by far the best studied drugs during CAPD. Although there have been a large number of publications concerning CAPD, the number of reports concerning the pharmacokinetic aspects of CAPD has been rather small. 6 During episodes of peritonitis antibiotics are commonly administered intraperitoneally, thereby obtaining a high concentration in the peritoneal cavity. This procedure may be accompanied by an intravenous loading dose to obtain adequate tissue concentrations. In determining dosage regimens of drugs during CAPD it is essential to have (at least some) knowledge of the implications various pharmacokinetic parameters have on the efficacy of different dosage regimens. The efficacy of each dosage regimen will depend upon the proper selection of loading dose, maintenance dosage and frequency of drug administration. Especially with potentially toxic drugs such
as the aminoglycosides it is important to obtain peritoneal, and tissue concentrations that are high enough, but not too high, to avoid toxicity problems. PERITONEAL
TRANSPORT
The transfer of solutes from blood to dialysate is determined by several factors. A solute has to pass between the endothelial cells of the peritoneal capillaries or go through these cells. Before it reaches the dialysate it has to pass the capillary basement membrane, the interstitial space and the mesothelium. 7 The major barriers appear to be the endothelial cell junctions and the interstitial space. The most important process involved in solute transport from blood to CAPD solution is diffusion and to a lesser extent ultrafiltration. The diffusion of a given solute depends upon the existence of a concentration gradient between blood and dialysate, membrane area and membrane permeability, l~ophilicity, charge, protein binding and solute size. ~ The second pi'ocess, ultrafiltration, is dependent on the presence of a hydrostatic or an osmotic pressure gradient, which forces all solutes through the barrier. Solutes with a very high molecular weight cannot be filtered and will not be influenced by this process. Peritoneal blood flow influences the efficacy of CAPD. Systemically or intraperitoneally administered vasodilating drugs such as dipyridamole, prostaglandin E2 or prostacyclin significantly improve peritoneal clearance rates, 9tt not only by increasing peritoneal blood flow, but also by making the capillary wall thinner by stretching it in all directions because of the vasodilating effect, thereby making it more permeable. The usual exchange volume of CAPD solutions is two litres; a further increase in volume might be painful to the patient. Lower exchange volumes will result in a reduced mean peritoneal clearance rate. Depending on the osmolarity of the CAPD solution the volume may increase considerably during the applied dwell time; this has consequences for the role of ultrafiltration in the solute transport as well as for the pharmacokinetic models to be used. The rate of transport of solutes across the peritoneal membrane correlates with the inverse square root of the molecular mass. So the clearance of a solute with a molecular mass of 200 will be two times as high as the
*Department of Clinical Pharmacy, Medical Centre Alkmaar, Van Everdingenstraat I8, 1814 HA Alkmaar, The Netherlands. w
230
Vol. 6 - I984
clearance of a solute with a molecular mass of 8o0. During the dialysis procedure the concentration gradient between blood and dialysate will steadily decline. Therefore the peritoneal clearance rate will depend upon the dwell times used in the CAPD procedure. Nolph et al. showed that with various dialysis solutions, only very highly diffusible solutes such as urea are approaching equilibrium at four hours. Net solute removal continued throughout the entire period for most solutes.n Dwell times longer than six hours may result in a significant decrease in the mean peritoneal clearance rates, n 13 For high molecular weight solutes, with peritoneal clearance rates that are much lower, dwell time will not significantly influence the mean peritoneal clearance rate, because it will take much longer than six hours to approach equilibrium between blood and
Pharmaceutisch Weekblad Scientific Edition
peritoneum, although we have found that even for gentamicin, which has a relatively low peritoneal clearance rate of about 2 ml/min, dwell times longer than six hours result in a decrease in the mean peritoneal clearance rate (see below). Because of this the peritoneal clearance rate is always expressed as the mean peritoneal clearance rate, which can be approximated by the following expression; assuming that no drug is administered intraperitoneally: CIcAPD =
VCAPD X CCAPD
t x 1/2(C~r.to 5- C~r.tl)
(eq. I)
In which CIcAPD represents the mean peritoneal clearance rate, VCAPD and CCAPD represent the outflow volume and the concentration of solute in this outflow solution, C~r.toand C~r.t, are the concen-
TABLE I. Pharmacokineticparameters after systemic drug administration* tlh lit. (h)
Gentamicin Tobramycin Cefamandole Cefazolin Cefotaxime Cefoxitin Ceftazidime Ceftizoxime
Cefalexin Moxalaetam (Latamoxef) Vancomycin Rifampicin Trimethoprim
Sulfamethoxazole Flucytosine Cimetidine Digoxin
Digitoxin Quinidine Furosemide
Phenytoin
tlh lit. ESRD (h)t
2 -4 2 -4 2 -4 2 -3 2 -3 2 -3 o.5-I.5 i .5-2 i .5-2 1 -1.5 o.75-I 2 -3 1.5-2 1..5-2 1.5-2 L5-2 i 1.5-2.5
5o-6o 50-60 50-60 50-70 50-70 50-70 7-18 20-30 20-30 2-3.5 5-20 9 30-35 3o-35 3o-35 3O-35 30-40 20-30
1.5-2. 5 4 -8 4-8 4-8 i .5-5 8 -16 8 -16 9 -II 2.4-6 2.4-6
20-30 200-240 200-240 200-240 3-5 24-46 24-46 IO-5O 75-25o 75-250
1.4-2.4 1.4-2.4 1.4-2.4 3o -40 30 -40 3 ~ -40 3o -40 168 -I92 4 - 12 o.5-1
3qo 3-IO 3-1o 85-1oo 85-IOO 85-1oo 85-1oo 2oo 4-12
lO -30
1o-3o
tlhc^pD (h) 27.4 + 11.7w 36 +9.0 7.7 34.8+I8.O 39.5+I7.9 io.4_+7.3 33.1 -+9.8 3.1 + I..3 7.8+2.7 5. i-2o.8 I2.5-+6.6 9 -+6.7 I0.2• 8.6• .16.5 11 16.7-t"2.1 77 -+27 90 -+24 61.5 8.5 94 107 +33 34 -+II
Clp (ml/min)
6.8 8.0+2.5 7.6+3.1 20 +6.2 5.7 +0.6 7.8 87.2+35 . 1 20.4-+3.9
2.94+0.39
20.2+6.9% in 24 h
3.8 +I.O 1.1 +0.8 3.2 + I . 6 1.oo-+o.32
x6.5-26.4% in 24 h
1.44+0.67 3.0 -+1.o
I7.1 +7. 4 3o + I I . 7
2.8 -+0.7 4.o -+i.o
18.5 -+6. i
2.3 + 1.4 2.6 2.8 2. 7 -+0. 5 1.4 -+0.95 1.35• I.l
7.3-+2.3 % in 24 h
7.0+2.7% in 6 h
4.8-+2.1% in 6 h
10.6-+2.0 9.8• 6.4+1.1 3 -+0.24
lO% in 24 h 23. 4 in 24 h 17.4-+3. I < 6% in 24 1.8% in 32 h IO.6% in 32 h
' 1.3----.0.3 32 ~ I 0
I67 -+2o
4.3
191 +55
5.4 lO.5 + 1.2 I1.6-+3.3
Recovered in dialysate
I2.O-+6.3
6.9•
89-2 97.9
ClcAn~ (ml/min)
28.4 I2.6
154.2
2.7 -+0.9 4.I 4.2 -+3.I 3.o -+[.o 2.74 2.o 3.9 +1.3 0.7 -+o.3 o.79
0.50"4-0.05 o.5o+o.lo 1.6 -1.77
approx. 20% in 6 h 15 mg/l (dose 1 g) 37 mg/l (dose 2 g) L6% in 24 h 1. 5 mg/l (dose 600 rag) 2.3_+1.4% in 24 h I% in 24 h 3.1% in 24 h < 2% in 24 h < 2% in 24 h 0.9-+0.25% in 24 h o.55-+o.05% in 24 h 5% in 24 b
*Most data were obtained after single dose intravenous administration. In case of cefalexin and furosemide a single dose was used and in case of digoxin, digitoxin, quinidine and phenytoin data were obtained in a-steady-state situation after administration.
V o l . 6 - I984
Pharmaceutisch Weekblad Scientific Edition
trations of solute in serum at the start and termination of exchange, ~4 t is the mean time of exchange. If we assume that infusion and drainage rate are constant and that the area available for mass transfer is proportional to the volume of fluid in the peritoneal cavity, t can be expressed as: t
=
tdwet,
+ l/z(ti + tr)
(eq. 2)
in which taweltrepresents the dwell time used, and ti and tr the times of infusion and removal of the dialysis solutions respectivelyJ 4 The formula on peritoneal clearance is only valid in a limited number of pharmacokinetic models. C~c~,tois often obtained by extrapolation, which is not always permitted. Many studies use the mid-dialysis concentration instead of the average of initial and end concentrations. A model independent formula, using the AUC (see below) should therefore be preferred. Vd,,~ (I/kg) Gentamicin
0.30+0.08 0.22-+0.07 0.24
Tobramycin Cefamandole Cefazolin Cefotaxime Cefoxitin Ceftazidime Ceftizoxime
Cefalexin Moxalactam (LatamoxeO
0.23-+0.06 0.34--+0.06 o.25_+o,o8 o. 19_+o.o2 24.6_+6.7 I 0.27_+0.05 o.23_+0.05 18.7_+4. 5 l 0.27_+0.07 0.22_+0.04
0.21-+O.O1 Vancomycin o.73-+o.x Rifampicin Trimethoprim
Dwell time (h) + volume (1) 6 h/2 1 8 h 6 h 4.5-8.5 h 4 h/2 1 6 hi2 1 3 x 4 h, 12 h/2 1 4.5-8.5 h 6 h/2 1 6 h 6 h/2 1 6 h 6 hi2 1 6 h/2 1 6 h/2 I 3 x 4 h, 12 h/2 1 6 h/2 1 6 h/2 I 4 h/2 I 6 h 3 x 4 h, 8 h/2 I 3 x 4 h, 8 h/2 I
1.28_+o.32
Sulfamethoxazole 0.17+0.22 Flucytosine Cimetidine o.96+o.21
6 4 3 4 6 6
h/2 1 h x 4.5 h, 8.5 h/2 I h/2 1 h/2 I h
Digoxin
Digitoxin Quinidine Furosemide
6 h/2 1 4-6 h/2 I 6 h/2 1 6 h/2 1 4 h/2 1 4-6 h/2 I
23I
A more fundamental property of the peritoneal membrane is the overall mass transfer coefficient or theoretical instantaneous clearance rate, which represents the clearance rate if a maximal concentration gradient is maintained. This can be used in defining changes in membrane permeability characteristics. Another important factor is the binding to serum proteins. Only the unbound fraction of a solute will be available for diffusion to the peritoneum. Therefore drugs with a high degree of protein binding will generally have low peritoneal clearance rates. On the other hand a high degree of protein binding will have a positive influence on the absorption of intraperitoneally administered drugs to blood by maintaining a high concentration gradient between the peritoneum and the free fraction in blood. The pharmacokinetic parameters found after systemic and after intraperitoneal administration of
Number of Peritonitis patients
% Protein binding (lit)
Molecular weight
References
5 7 I 4 6 6 5 6 6 8 6 6 8 t2 5 8 5 .4 z 8 5 4 t Io lo 8 8 ! l 6 t 6 7 5 I 5 8 i II 4 2
o-lo o-~o o-lo o-lo o-lo O-lO 6o-75 80-90 8o-9o 30-4 ~ 55-75 to 30 3~ 30 30 Io-15 35-60
approx. 14oo approx. 14oo approx. 14oo 467 467 467 462 454 454 455 427 546 383 383 383 383 365 542
19 43 18 20 15 I6 z7 44 45 20 46 47 48 49 5~ 5 ! 52 53 54 45 21
35-60 approx. IO approx, lo approx. Io 60-90 40-70 4o-70 6o-7o 4 4 Io-2• 10-2o 1o-2o 2o-4o 2o-4o 2o-4o 20-40 90-97 80-90 9t-99
542 t448 1448 1448 823 290 290 253 129 t29 252 252 252 500 500 500 500 765 324 331
55 25 26 27 28 29 29 3~ 30 32 35 37 56 38 39 57 58 59 60 61 61 62 63
no yes yes no no no no yes no no no no no no no no no yes no yes no no no no yes yes no no no no no no no no no no yes no
Phenytoin i'ESRD = end stage renal disease. w values are expressed as mean + SD, if possible the range is also given.
85-99
252
64
232
Vol. 6 - I984
X
various drugs to CAPD patients are shown in Table I and Table n respectively. PHARMACOKINETIC
PARAMETERS
Systemic administration The elimination half-life of a given drug during CAPD treatment (tl/2cAPO), was determined from the 13-elimination phase of the plasma concentration versus time curve, "using the open two-compartment model. Clp (ml/min) represents the plasma clearance (or total body clearance), in most kinetic studies derived from the expression: dose Clp = AUC0-|
(eq. 3)
wllere AUCo-| is the area under the curve from time o to infinity, determined by the trapezoid rule. CIcAPD (ml/min)represents the peritoneal clearance, which was calculated as:
Pharmaceutisch Weekblad Scientific Edition
CIcAPO = AUC,,-,2
(eq. 4)
in which X is the total amount of drug collected in the dialysate over a given period a n d AUCtl_t ~is the area under the curve over the same time period. Vdarea was calculated from the expression: Vd a,oa =
dose AUCo-| x kc,
(eq. 5)
in which kr is the elimination rate constant; Vda,~ais expressed as volume per kg bodyweight. Intraperitoneal administration The percentage absorbed after intraperitoneal a d m i n i s t r a t i o n is c o m m o n l y o b t a i n e d b y s u b t r a c t i n g from the amount of drug initially instilled the total a m o u n t o f d r u g t h a t w a s p r e s e n t in t h e first p e r i t o n e a l o u t f l o w . T h i s p r o c e d u r e a s s u m e s t h a t t h e r e is no decompensation of drug over the same time period. Yet very few authors make clear statements
TABLEII. Pharmacokineticparameters after intraperitoneal drug administration
Gentamicin
Netilmicin Tobramycin
Cefazolin
Dose (mg) + dialysate volume (1)
Dwell time (h)
% Absorbed*
Achieved serum concentration (mg/I)t
Peritonitis
Number of Refepatients rences
15 mg/2 1 15 mg/2 I I mg.kg-'/2 l 15 mg/2 I 15 mg/2 1 I00 mg/2 1 1o mg/2 I 1o mg/2 1 I5 mg/2 1 20 mg/2 I
8 8 6 6 6 6 5.6, 5.8 6
85.0_+ 19.7 63.9_+27.6 84 79.3_+2.6 64.0+4.8 49.o+14.7
o.57+0.18 (SD) o.63_+o.17 (SD) 3.52__.2.22 (SS)
yes no no yes no no yes yes
5 7 5 5 5 7 5 14
xo mg/2 1
6
480./0 (SS)
15 mg/2 1, a f t e r xoo mg/2 I
6
85% (SD)
loading dose IO mg.kg-V2 I 1 8/2 I, later 50o mg/2 l
Cefamandole I g/2 1 Cefotaxime I g/2 1 250 rag/2 I 250 mg/2 I
3 x 4 + I x ~2 73.7 (4 h) 6 88 (SD) 65 (SS) 6 71.7-+12.8 12, 6, 6 (tV2 absorb. 1.43+o.88 h) 6 2
I g/2l
2
500 mg/2 I
4-8
Ceftazidime
600 mg
Ceftizoxime
500 mg 500 mg/2 1 750 mg/2 1
4 6 6 6 5-8
Cefuroxime Ampicillin Azlocillin Oxacillin
1 g/2 I I g/2 1 I g/2 1
5-8 5-8 5-8
3.9 + 1.5 (SD)
4-5 (ss) 2.5 (ss)
3.3 (SS) 4.5 (SS) 1.3+o.1 (day i) 2. i +0.2 (day 2) 3.7+0.2 (SS)
65 65 I9 66 66 43 22 67
yes
20
yes
20
36 (55) 54.8+6.7 (SD) 11o.9+6.7 (SS) 3]-8+5.4 - ' approx. 2o (SD)
no
45
no no
46
8.~-t4.9 (SD)
yes yes yes yes
46 68 68 69
no
48
no no
49 53 54
5.5. 35 6.9
89.9 (day I) 66.7 (day 12) 7.1. 5o.8+t9.o 72.5+8.9 86+5 therapeutic 78+ 4 3~ (SS)
yes
yes
30 (SS)
no
approx. 50 (SS) 30-35 (SS) approx. 45 (SS) approx. 25 (SS) approx. 2.5 (SS) approx. 2.5 (SS)
yes
*All values are expressed as mean + SD, if possible the range is also given. tSD = single dose; SS = steady state.
20
44
22 22
no
yes
23
no
yes no
23
Vol. 6 - 1984 Pharrnaceutisch Weekblad Scientific Edition about the stability of the drugwhose pharmacokinetics were evaluated. In a recent study we have found most cephalosporins to show a considerable decomposition after six hours at 37~ (unpublished observations) so some studies may have overestimated the amountof drug absorbed after intraperitoneal administration. DISCUSSION
Aminoglycosides The necessity of obtaining high serum and tissue concentrations of antimicrobial agents used in the therapy of CAPD-associated peritonitis is still not clear, but it does protect the patient from developing a potentially dangerous sepsis. Generally only a small portion of systemically administered aminoglycosides is removed by CAPD, although the clearance rates show a considerable variation between different studies. ~517 These differences may have been caused by variations in study populations, residual renal function, dwell times and dwell volumes. We administered I2o mg gentamicin intravenously to an end stage renal disease patient on CAPD therapy (Dianeal | 2.27% glucose) and studied the influence of dwell time and dialysate volume on the mean peritoneal clearance rate. With three 4-5 h exchanges and a nightly dwell time of Io.5 h dialysate volume was 500 ml during five days after the administration of gentamicin. Later a second intravenous bolus injection was given and dialysate volume was increased to I i. The following mean peritoneal clearances were found: 0.45+0.09 .ml/min (long dwell time, 500 ml); o.96+o.x8 ml/min (long dwell time, I 1); x.45+o.34 ml/min (short dwell time, 500 ml) and 2.04+0.32 ml/min (short dwell time, ~1) (R.J., unpublished observations). All values are expressed as the mean clearance over five days + standard deviation. Both gentamicin and tobramycin have long halflives in patients on CAPD, ranging from 27.4 to 39.5 hours (Table I). Blouin etal. found a half-life of 7.7 h in a three year old girl, TM but this very short half-life may partly have been caused by the co-medication (hydralazine, diazoxide). Somani et al. showed that the transfer of gentamicin from peritoneum to blood is far greater than the transfer of gentamicin from blood to the peritoneum. 19 The same is true for tobramycin; 16"17 the reasons fo r these dtfferences are unknown, but the magnitude of concentration gradient and differences in membrane surface area at the two sides of the peritoneal membrane may contribute to the unidirectional absorption of both gentamicin and tobramycin. The presence of peritonitis tended to result in a more rapid absorption o f gentamicin from the peritoneum to the blood (85.0+ I9.7% absorbed in eight hours in patients with peritonitis and 63.9+27.6% in patients without signs of peritonitis).
233 The kinetics of aminoglycoside elimination after parenteral administration are variable and appropriate dosage schedules should always be accompanied by determinations of serum or plasma levels in order to prevent potentially toxic concentrations. Various recommendations have been made: intraperitoneal administration of 5-IO mg/l combined with an intravenous (80 mg) or intraperitoneal (12o mg) loading dose should result in good tissue and peritoneal concentrations, although determination of serum levels always remains necessary. 16 17 20 Cephalosporins Staphylococcus aureus and Staphylococcus epidermidis are the most common causative organisms in CAPD-related peritonitis. Most of the first generation cephalosporins have excellent in vitro and in vivo activity against these organisms as well as against most of the Gram-negative bacilli that occasionally cause peritonitis in CAPD patients. The activity of the third generation cephalosporins against the Staphylococci is much less, but their activity against Gram-negative organisms is markedly improved. For these reasons the cephalosporins have become frequently used in the treatment of peritonitis. Cephalosporins have a-much wider therapeutic margin than aminoglycosides. Toxicity occurs only at very high serum concentrations and routine monitoring of serum levels is not necessary. Cephalosporins show great variability in their pharmacokinetic behaviour. The mean peritoneal clearance x;aries from I ml/min for cephazolin to about 4.ml/min for ceftazidime and cefizoxime. Although the peritoneal clearance contributes only a small. portion to total body clearance, the elimination half-life of most cephalosporins is lower in patients on CAPD than in untreated patients with end stage renal disease. The peritoneal clearance of cephalosporins with a high degree of protein binding tends to be lower than in the cephalosporins with a low degree of protein binding, but protein binding is influenced by renal function and in end stage renal disease the protein binding of most drugs is markedly reduced. Little is known about the influence of peritonitis on the pharmacokinetic behaviour of the cephalosporins. KOnigshausen et al. demonstrated a greater clearance (4.8 ml/min) in a patient with peritonitis compared with patients without.peritonitis (mean peritoneal clearance 2.6 ml/min), ~' but the number of patients was far too small to draw any conclusions. Dosage recommendations for cephalosporins vary widely. In most cases intraperitoneal administration of 250-500 mg per exchange will lead to adequate serum and dialysate levels. Penicillins Only limited data on the pharmacokinetics of
234 penicillin derivatives during CAPD are available. Thomae et al. found, within 24 h, fairly constant serum levels of ampicillin, azlocillin and oxacillin after repeated intraperitoneal administration, z223 These levels were within the (wide) therapeutic margin and lacked the fluctuation normally seen after oral or parenteral administration. Vancomycin There is a trend towards an increased number of Staphylococci being resistant to penicillins and cephalosporins. Most of these resistant Staphylococci are susceptible to vancomycin. Although vancomycin is rapidly absorbed after intraperitoneal administration (5o-60% absorbed after four to six hours dwell time)~2426 the transfer from blood to the peritoneal dialysate occurs, at a slow rate, despite the low volume of distribution and the low percentage of protein binding. The high molecular weight of vancomycin (I448)'may partly be the reason. Mean serum half-lives of sixty to ninety hours have been reported,ZS2s and accumulation of vancomycin with the possibility of causing ototoxicity, should be prevented. Pancorbo suggested that, after a loading dose of I g vancomycin in 21 of dialysate, the addition of io-20 mg/l of the drug to each bag of dialysate would maintain therapeutic serum levels by equalizing the concentration gradient between serum and dialysate fluid. 24 The problem with this dosage regimen is that vancomycin is only. available in ampoules of 500 mg. Co-trimoxazole Oral administration of co-trimoxazole (trimethoprim+sulfamethoxazole) results in poor intraperitoneal concentrations, as less than 3% of trimethoprim and 2% of sulfamethoxazole reach the peritoneal cavity. Intraperitoneal administration results rapidly in high serum concentrations? As serum half-lives of both trimethoprim and sulfamethoxazole are prolonged during CAPD, care must be taken to avoid accumulation of the drugs after intraperitoneal administrationfl 3oIntraperitoneal administration seems to be the preferable route of administration, but not enough pharmacokinetic data are available to justify dosage recommendations. Glasson administered 400 mg sulfamethoxazole and 80 ifig trimethoprim to each of four daily exchanges during two weeks, and half that dose for the two following weeks to 2I patients. Five patients developed co-trimoxazole related side effects, but no plasma levels were determined. 3~ Antifungal agents As fungal peritonitis is a rare complication of CAPD only little experience with the management and pharmacokinetics of antifungal drugs is available. Clark et al. found in two of their patients that, although the cultures of peritoneal fluid became
Vol. 6 - 1984 Pharmaceutisch Weekblad Scientific Edition negative, the catheters were still heavily colonized with moulds after removal of the catheter. 32There is general agreement that fungal peritonitis is an indication for early catheter removal, which appears to be the most effective therapy. Ketoconazole penetrates poorly from the blood to the peritoneal fluid and is unlikely to be of benefit in CAPD peritonitis caused by fungi. 3233 Amphotericin B, which is highly protein bound (more than 9o%) and circulates in the blood in a complex of high molecular weight (200 o00-3o0 ooo) also poorly penetrates the peritoneal fluid from the blood. Muther could not detect amphotericin B in the dialysate after systemic administration, 34Kerr et al. only detected just measurable levels in the dialysate of CAPD patients) 2 Intraperitoneal administration of amphotericin B must often be abandoned because of abdominal discomfort. 35Khanna et al. proposed that when amphotericin B is used intraperitoneally the dialysate should be adjusted to neutral pH to prevent aggregation. 36 Flucytosine easily passes from the blood into the peritoneal fluid. Lempert suggests an initial oral dose of 30 mg/kg followed by 15 mg/kg once daily, which would provide therapeutic drug levels in both serum and dialysate. 35 Cimetidine Although cimetidine is only 3o% protein bound and has a low molecular weight, all properties favouring a high dialysis clearance, the available data show low clearance rates for both CAPD (approximately 4 ml/min), intermittent peritoneal dialysis (5-Io ml/min) and haemodialysis (approximately 28 ml/min) ,37-41rates which are only a fraction of the normal total body clearance of approximately 655 ml/min and the normal renal clearance of approximately 375 ml/min. Pizella et al. found about 74% of the total body load of cimetidine in post mortem material to be located in skeletal muscle, whereas only 3.75 % was present in thecii'culation and available for dialysis: ~ These data indicate no need for adjusting the conventignal renal failure dosage regimen in patients undergoing CAPD. CONCLUSIONS
There is only a limited number of drugs whose pharmacokinetics during CAPD are well known. Only the cephalosporins and the aminoglycosides have been studied in detail, but little is known about the pharmacokinetics of other antibiotics that may be used in the treatment of peritonitis, such as flucloxacillin and rifampicin. Many of the dosage schedules used in the treatment of CAPD-associated peritonitis are based on empirical grounds. A better knowledge of the pharmacokinetics of these antibiotics or antifungal agents is needed-to give dosage recommendations that are more efficacious and/or less expensive.
Vol. 6 - 1984 Pharmaceutisch Weekblad Scientific Edition
Acknowledgement The authors thank Dr. A. Steenhoek, hospital pharmacist, and Dr. M.J. NubO, D e p a r t m e n t of Haemodialysis, for their critical review of the text. REFERENCES
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