EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1991, Vol. 16, No. I, pp. 49-52
Pharmacokinetics and tissue concentrations of cefazolin in pediatric patients undergoing gastrointestinal surgery M.e. NAHATA, D.E. DURRELL, M.E. GINN-PEASE and D.R. KING Colleges ofPharmacy and Medicine, Ohio State University and Wexner Institute for Pediatric Research, Children's Hospital, Columbus, Ohio, USA
Receivedfor publication: May 31,1990
Keywords: Cefazolin, pediatric patients, gastrointestinal surgery,pharmacokinetics, tissue concentrations
SUMMARY Limited information is available on the pharmacokinetics and tissue penetration of cefazolin in pediatric patients. Nine children (age 0.8-10 years) undergoing gastrointestinal operations were studied. A single dose of cefazolin, 15-26 mg/kg was given i.v. over 2-3 min at the time of induction of anaesthesia. Multiple (5-8) blood samples were collected during the operative procedure and in the recovery room. TISsue samples from the rectus abdominis muscle were obtained at the time of incision, during surgery, and at closure. The concentration of cefazolin was measured by a high performance liquid chromatographic method. Peak serum concentrations of cefazolin ranged from 85.8-269.4 meg/mI. Serum and tissue concentrations at incision were 50.5-169.9 mcg/mI and 1.8-29.7 mcg/g; at closure the serum and tissue concentrations ranged from 17.3-60.9 mcg/ml and 1.19-29.70 mcg/g, respectively. Total clearance, apparent distribution volume, and elimination half-life of cefazolin were 1.43 ± 0.54 mlIminlkg, 0.08 ± 0.03 Ukg, and 1.68 ± 0.55 h respectively. TISsue concentrations of cefazolin were maintained above its minimum inhibitory concentrations against common susceptible pathogens. Hence, the current dosing regimen of cefazolin is adequate to protect against infection in pediatric patients undergoing gastrointestinal surgery.
INTRODUCTION Cefazolin is the most commonly used parenteral cephalosporin. The drug is active against a variety of both gram-positive and gram-negative microorganisms, including Streptococcus pneumoniae, Staphylococcus aureus, Group A beta-hemolytic streptococci, Escherichia coli, Haemophilus irftuenzae, Klebsiella sp., Proteus mirabilis and some enterococci (1). Cefazolin is one of the most frequently used prophylactic antibiotics in pediatric patients undergoing surgery. The dose should be given 0.5 to 1 h prior to the start of surgery so that adequate levels are present in serum and tissue at the time of initial Please send reprint requests to : Dr Milap C. Nahata, College of Pharmacy, Ohio State University, 500 W. 12th Avenue, Columbus, OH 43210, USA
surgical incision (1). The prescribing information suggests the dosage guidelines of cefazolin for the treatment of various infections in pediatric patients (1). However, no dosage recommendations are made for surgical prophylaxis in infants and children (1), perhaps due to a lack of pharmacokinetic data of cefazolin in pediatric patients. No previous studies have provided pharmacokinetic parameters (e.g., clearance and distribution volume), and tissue concentrations of cefazolin in pediatric patients undergoing surgery. These data would be required to assess the adequacy of commonly used doses of cefazolin in pediatric institutions. We evaluated the pharmacokinetics and tissue concentrations of cefazolin in children undergoing gastrointestinal surgical procedures. The hypothesis for the study was that the tissue concentrations of cefazolin must exceed its minimum inhibitory
Eur. J. DrugMetab. Pharmacokinet., 1991, No.1
50
Table 1: Pharmacokinetics of cefazolin in pediatric patients Patient
Age years
Dose mg/kg
Maximum
Timeto peak
serum cone.
h
mcglml
Total clearance mllminlkg
Distribution volume
Elimination half-life
lIh
h
1
2.0
24.5
190.0
0.2
1.3
0.08
1.4
2
9.0
25.2
262.0
0.2
1.0
0.06
1.6
3
10.0
24.2
97.6
0.2
2.4
0.14
1.1
4
0.8
23.1
102.0
0.2
2.2
0.13
1.2
5
2.3
23.8
85.8
1.0
1.6
0.09
1.7
6
0.8
15.1
89.1
0.5
1.0
0.06
2.3
7
9.2
25.7
202.4
0.2
1.3
0.08
2.5
8
8.9
26.1
269.4
0.2
1.2
0.07
1.0
9
0.8
16.6
136.0
0.2
0.9
0.05
2.3
X
4.9
22.7
137.1
0.3
1.4
0.08
1.7
± 1.2
±4.0
±87.9
±0.2
±0.5
±0.03
±0.6
±SD
concentration (MIC) against the common susceptible pathogens to prevent postoperative infections.
MATERIALS AND METHODS The study was approved by the Human Subjects Research Committee, Children's Hospital, Columbus, Ohio and a written informed consent was obtained from the parents or legal guardians prior to the enrollment into the study. Nine pediatric patients (age 0.8-10 years) undergoing gastrointestinal surgeries including colostomy closures, Duhamel procedures, and Nissen fundoplication were included. The physical examination and laboratory data showed no evidence of liver or renal disease. A single dose of cefazolin was given intravenously over 2-3 min at the time of induction of anaesthesia. The dose ranged from 15-26 mglkg (Table I). Multiple blood samples were obtained during surgery and the recovery period. The blood samples were collected prior to drug administration (0 h) and at 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 h after the dose. The samples were centrifuged and the serum was separated and stored at -70'C until analysed. Tissue (muscle and adipose) samples from the rectus abdominis were obtained at the time of incision, during surgery and at closure. The samples were rinsed in sterile 0.9% sodium chloride solution, blotted dry with gauze and frozen at -70'C. These samples
were weighed, minced and 0.01 M sodium phosphate buffer was added in a 1:2 w/v ratio. This mixture was homogenised for 3 min in a tissue grinder and centrifuged at 11,000 g under refrigeration for 5 min. The supernatant was collected and divided into two parts. One portion was used for the measurement of cefazolin concentration and the other to correct for blood contamination using the method of Lowry and Hastings (2). Cefazolin concentrations in serum and tissue samples were measured by a high performance liquid chromatographic (HPLC) method (3). Pharmacokinetic parameters were determined after the administration of a single dose as follows: area under the serum concentration-time curve (AUC) was calculated by the trapezoidal method and extrapolated to infinity; total clearance was determined from DoselAUC; elimination rate constant (Ke) was derived from the linear regression analysis of log serum concentration-time data; apparent volume of distribution was obtained from ClearancelKe; and elimination half-life was calculated from 0.693/Ke.
RESULTS The pharmacokinetic data of cefazolin are presented in Table I. The peak serum concentration ranged from about 86-269 mcglml after-the dose of 15-26 mg/kg. In general, the peak occurred at 0.2 h after the dose. The total body clearance, apparent volume of
51
M. C. Nahata et al., Cefazolin in G-I surgerypatients Table 11 : Cefazolin tissue and serum concentrations At incision
During surgery
Tissue cone.
Serum cone.
Sampling
Patient
(meg/g)
(mcg/ml)
time (h)
1
17.3
89.9
1.0
2
4.6
169.9
3
0.8
50.5
4
1.2
5 6
At closure
Tissue cone. Serum cone. Sampling mcg/g
(mcg/ml)
Tissue cone. Serum cone. Sampling
time (h)
(meg/g)
(mcg/ml)
time (h)
ND
ND
ND
13.4
50.4
2.0
0.5
4.9
79.7
1.0
5.5
60.9
2.0
1.0
9.8
45.0
1.5
6.3
36.6
2.0
75.4
0.5
1.9
54.1
1.0
5.0
35.8
2.0
58.4
85.8
1.0
47.2
56.0
2.0
29.7
23.8
3.8
37.6
89.1
0.5
ND
ND
ND
9.8
43.0
2.0
1.0
1.2
55.8
2.0
ND
2.7
112.7
1.0
7
6.2
146.0
0.5
8.5
107.8
8
4.4
168.0
0.5
ND
ND
X
16.8
110.0
0.7
14.5
68.5
1.3
9.3
55.4
2.1
±0.2
± 18.6
±25.4
±0.4
±8.5
±27.0
±0.7
±SD
± 19.6
±42.5
ND - not determined
distribution and elimination half-life ranged from 0.9-2.4 mlIminlkg. 0.05-0.14 lIkg, and 1.0-2.5 h. respectively. The concurrent tissue and serum concentrations at incision during surgery and at closure are presented in Table II. At incision, the tissue and serum concentrations ranged from about 0.8-58.0 mcg/g and 51-170 mcg/ml, respectively. During surgery. the tissue and serum concentrations were 1.9-47.2 meg/g and 45-108 meg/mI respectively. At closure. the tissue and serum concentrations ranged from 1.2-30.0 meg/g and 24-113 mcg/ml, respectively. The mean percentage ratio of the tissue/serum concentration was 15% at incision. 21% during surgery, and 17% at closure. The mean duration of the operative procedure was about 2 h. Repeat doses of cefazolin were not administered during surgery. No adverse effects occurred due to cefazolin in any patient
DISCUSSION Cefazolin is one of the most commonly used antibiotics for surgical prophylaxis in pediatric patients but no dosage guidelines are available for its use in this patient population. However, specific dosage guidelines are available for the treatment (not prophylaxis) of various infections in children. including respiratory. urinary tract, skin and skin
structure, biliary tract, bone and joint, genital. and septicemia and endocarditis (1). The manufacturer recommends a dosage regimen of 25-50 mglkg/day in divided doses (1), and a frequently used source suggests 50-100 mglkg/day divided in three doses (4). The lack of dosing information for surgical prophylaxis. in part, can be attributed to extremely limited data about the pharmacokinetics and tissue concentrations of cefazolin in pediatric patients. This investigation is the first to determine the serum and tissue concentration at incision, during surgery and at closure in patients undergoing gastrointestinal surgeries. Although substantial interpatient variation occurred, our data showed that the tissue concentrations were maintained above the MIC against the common susceptible pathogens throughout the procedure. Thus. our current practice of using cefazolin as described in this study appears adequate to protect against infection in infants and children undergoing gastrointestinalprocedures. Limited data are available about the pharmacokinetics of cefazolin in children. A study in 8 children with osteomyelitis has reported an elimination half-life of 1.7-1.8 h (5), which is consistent with the values in our patients. Total body clearance and distribution volumes have been reported only in newborn infants; clearance ranged from 0.53-1.1 mlIminlkg and distribution volume from 0.21-0.34 lIkg in these infants (6). A comparison of these data with those of this study suggests that the
52
Eur. J. DrugMetab. Pharmacokinet., 1991, No.1
clearance was higher in our children, perhaps due to the maturation of the kidney, and the distribution volume was higher in newborn infants (age 2-28 days) due to their increased extracellular fluid volume as well as increased free (unbound) fraction of cefazolin in plasma. Although cefazolin was initially marketed in the USA in 1973, little is known about its clinical pharmacology in pediatric patients. This lack of knowledge of phannacokinetics is remarkable as it is widely used in children. The present data validate our current dosing regimen for surgical prophylaxis which seems appropriate and safe. Although cephalosporins generally have a wide margin of safety, specific studies should be done to evaluate the phannacokinetics and tissue concentrations of all antibiotics used for surgical prophylaxis in infants and children to prevent postoperative infections.
REFERENCES 1. Manufacturer's product infonnation for cefazolin (Ancef and K.efzol), Phylliciatt$' Desk Reference, 4300 edn., 1989. Medical Economics Co., Ine., Oradell, NJ pp. 1187-1189, 2037-2039. 2. Lowry D.H., HaWngll A.B. (1942) : Histochemical changes essociated with aging: methods and calculations. J. BioI. Chem., 143,257-264. 3. Dudley N.M, Nightingale C.H., Drezner AD., Low H.B., Quinti1iani R. (1984) : Comparative penetration of cefonicid and cefazolin into the atrial appendage and pericardial fluid of patients undergoing open-heart surgery. Antimicrob. Agents Chemother.,26,347-350. 4. Nelson J.D. (1989-90): Pocketbook of Pediatric Antimicrobial Therapy, 8th edn.. Baltimore, Willill11lll & Wilkins, p. 66. 5. TezlaffT.R., Howard J.B., McCracken G.H., Calderon E., Larronde J. (1978) : Antibiotic concentrations in pus and bone of children with osteomyelitis, J. Pediatr., 92, 135-140. 6. Deguchi Y., Koshida R., Nakashima E., et al. (1988): Interindividual changes in volume of distribution of cefazolin in newborn infants and il$ prediction based on physiological pharmacokinetic concepts, J. Pharm. ScL, 77, 674-678.
Pharmacokinetics and tissue concentrations of cefazolin in pediatric patients undergoing gastrointestinal surgery M.e. NAHATA, D.E. DURRELL, M.E. GINN-PEASE and D.R. KING Colleges ofPharmacy and Medicine, Ohio State University and Wexner Institute for Pediatric Research, Children's Hospital, Columbus, Ohio, USA
Receivedfor publication: May 31,1990
Keywords: Cefazolin, pediatric patients, gastrointestinal surgery,pharmacokinetics, tissue concentrations
SUMMARY Limited information is available on the pharmacokinetics and tissue penetration of cefazolin in pediatric patients. Nine children (age 0.8-10 years) undergoing gastrointestinal operations were studied. A single dose of cefazolin, 15-26 mg/kg was given i.v. over 2-3 min at the time of induction of anaesthesia. Multiple (5-8) blood samples were collected during the operative procedure and in the recovery room. TISsue samples from the rectus abdominis muscle were obtained at the time of incision, during surgery, and at closure. The concentration of cefazolin was measured by a high performance liquid chromatographic method. Peak serum concentrations of cefazolin ranged from 85.8-269.4 meg/mI. Serum and tissue concentrations at incision were 50.5-169.9 mcg/mI and 1.8-29.7 mcg/g; at closure the serum and tissue concentrations ranged from 17.3-60.9 mcg/ml and 1.19-29.70 mcg/g, respectively. Total clearance, apparent distribution volume, and elimination half-life of cefazolin were 1.43 ± 0.54 mlIminlkg, 0.08 ± 0.03 Ukg, and 1.68 ± 0.55 h respectively. TISsue concentrations of cefazolin were maintained above its minimum inhibitory concentrations against common susceptible pathogens. Hence, the current dosing regimen of cefazolin is adequate to protect against infection in pediatric patients undergoing gastrointestinal surgery.
INTRODUCTION Cefazolin is the most commonly used parenteral cephalosporin. The drug is active against a variety of both gram-positive and gram-negative microorganisms, including Streptococcus pneumoniae, Staphylococcus aureus, Group A beta-hemolytic streptococci, Escherichia coli, Haemophilus irftuenzae, Klebsiella sp., Proteus mirabilis and some enterococci (1). Cefazolin is one of the most frequently used prophylactic antibiotics in pediatric patients undergoing surgery. The dose should be given 0.5 to 1 h prior to the start of surgery so that adequate levels are present in serum and tissue at the time of initial Please send reprint requests to : Dr Milap C. Nahata, College of Pharmacy, Ohio State University, 500 W. 12th Avenue, Columbus, OH 43210, USA
surgical incision (1). The prescribing information suggests the dosage guidelines of cefazolin for the treatment of various infections in pediatric patients (1). However, no dosage recommendations are made for surgical prophylaxis in infants and children (1), perhaps due to a lack of pharmacokinetic data of cefazolin in pediatric patients. No previous studies have provided pharmacokinetic parameters (e.g., clearance and distribution volume), and tissue concentrations of cefazolin in pediatric patients undergoing surgery. These data would be required to assess the adequacy of commonly used doses of cefazolin in pediatric institutions. We evaluated the pharmacokinetics and tissue concentrations of cefazolin in children undergoing gastrointestinal surgical procedures. The hypothesis for the study was that the tissue concentrations of cefazolin must exceed its minimum inhibitory
Eur. J. DrugMetab. Pharmacokinet., 1991, No.1
50
Table 1: Pharmacokinetics of cefazolin in pediatric patients Patient
Age years
Dose mg/kg
Maximum
Timeto peak
serum cone.
h
mcglml
Total clearance mllminlkg
Distribution volume
Elimination half-life
lIh
h
1
2.0
24.5
190.0
0.2
1.3
0.08
1.4
2
9.0
25.2
262.0
0.2
1.0
0.06
1.6
3
10.0
24.2
97.6
0.2
2.4
0.14
1.1
4
0.8
23.1
102.0
0.2
2.2
0.13
1.2
5
2.3
23.8
85.8
1.0
1.6
0.09
1.7
6
0.8
15.1
89.1
0.5
1.0
0.06
2.3
7
9.2
25.7
202.4
0.2
1.3
0.08
2.5
8
8.9
26.1
269.4
0.2
1.2
0.07
1.0
9
0.8
16.6
136.0
0.2
0.9
0.05
2.3
X
4.9
22.7
137.1
0.3
1.4
0.08
1.7
± 1.2
±4.0
±87.9
±0.2
±0.5
±0.03
±0.6
±SD
concentration (MIC) against the common susceptible pathogens to prevent postoperative infections.
MATERIALS AND METHODS The study was approved by the Human Subjects Research Committee, Children's Hospital, Columbus, Ohio and a written informed consent was obtained from the parents or legal guardians prior to the enrollment into the study. Nine pediatric patients (age 0.8-10 years) undergoing gastrointestinal surgeries including colostomy closures, Duhamel procedures, and Nissen fundoplication were included. The physical examination and laboratory data showed no evidence of liver or renal disease. A single dose of cefazolin was given intravenously over 2-3 min at the time of induction of anaesthesia. The dose ranged from 15-26 mglkg (Table I). Multiple blood samples were obtained during surgery and the recovery period. The blood samples were collected prior to drug administration (0 h) and at 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 h after the dose. The samples were centrifuged and the serum was separated and stored at -70'C until analysed. Tissue (muscle and adipose) samples from the rectus abdominis were obtained at the time of incision, during surgery and at closure. The samples were rinsed in sterile 0.9% sodium chloride solution, blotted dry with gauze and frozen at -70'C. These samples
were weighed, minced and 0.01 M sodium phosphate buffer was added in a 1:2 w/v ratio. This mixture was homogenised for 3 min in a tissue grinder and centrifuged at 11,000 g under refrigeration for 5 min. The supernatant was collected and divided into two parts. One portion was used for the measurement of cefazolin concentration and the other to correct for blood contamination using the method of Lowry and Hastings (2). Cefazolin concentrations in serum and tissue samples were measured by a high performance liquid chromatographic (HPLC) method (3). Pharmacokinetic parameters were determined after the administration of a single dose as follows: area under the serum concentration-time curve (AUC) was calculated by the trapezoidal method and extrapolated to infinity; total clearance was determined from DoselAUC; elimination rate constant (Ke) was derived from the linear regression analysis of log serum concentration-time data; apparent volume of distribution was obtained from ClearancelKe; and elimination half-life was calculated from 0.693/Ke.
RESULTS The pharmacokinetic data of cefazolin are presented in Table I. The peak serum concentration ranged from about 86-269 mcglml after-the dose of 15-26 mg/kg. In general, the peak occurred at 0.2 h after the dose. The total body clearance, apparent volume of
51
M. C. Nahata et al., Cefazolin in G-I surgerypatients Table 11 : Cefazolin tissue and serum concentrations At incision
During surgery
Tissue cone.
Serum cone.
Sampling
Patient
(meg/g)
(mcg/ml)
time (h)
1
17.3
89.9
1.0
2
4.6
169.9
3
0.8
50.5
4
1.2
5 6
At closure
Tissue cone. Serum cone. Sampling mcg/g
(mcg/ml)
Tissue cone. Serum cone. Sampling
time (h)
(meg/g)
(mcg/ml)
time (h)
ND
ND
ND
13.4
50.4
2.0
0.5
4.9
79.7
1.0
5.5
60.9
2.0
1.0
9.8
45.0
1.5
6.3
36.6
2.0
75.4
0.5
1.9
54.1
1.0
5.0
35.8
2.0
58.4
85.8
1.0
47.2
56.0
2.0
29.7
23.8
3.8
37.6
89.1
0.5
ND
ND
ND
9.8
43.0
2.0
1.0
1.2
55.8
2.0
ND
2.7
112.7
1.0
7
6.2
146.0
0.5
8.5
107.8
8
4.4
168.0
0.5
ND
ND
X
16.8
110.0
0.7
14.5
68.5
1.3
9.3
55.4
2.1
±0.2
± 18.6
±25.4
±0.4
±8.5
±27.0
±0.7
±SD
± 19.6
±42.5
ND - not determined
distribution and elimination half-life ranged from 0.9-2.4 mlIminlkg. 0.05-0.14 lIkg, and 1.0-2.5 h. respectively. The concurrent tissue and serum concentrations at incision during surgery and at closure are presented in Table II. At incision, the tissue and serum concentrations ranged from about 0.8-58.0 mcg/g and 51-170 mcg/ml, respectively. During surgery. the tissue and serum concentrations were 1.9-47.2 meg/g and 45-108 meg/mI respectively. At closure. the tissue and serum concentrations ranged from 1.2-30.0 meg/g and 24-113 mcg/ml, respectively. The mean percentage ratio of the tissue/serum concentration was 15% at incision. 21% during surgery, and 17% at closure. The mean duration of the operative procedure was about 2 h. Repeat doses of cefazolin were not administered during surgery. No adverse effects occurred due to cefazolin in any patient
DISCUSSION Cefazolin is one of the most commonly used antibiotics for surgical prophylaxis in pediatric patients but no dosage guidelines are available for its use in this patient population. However, specific dosage guidelines are available for the treatment (not prophylaxis) of various infections in children. including respiratory. urinary tract, skin and skin
structure, biliary tract, bone and joint, genital. and septicemia and endocarditis (1). The manufacturer recommends a dosage regimen of 25-50 mglkg/day in divided doses (1), and a frequently used source suggests 50-100 mglkg/day divided in three doses (4). The lack of dosing information for surgical prophylaxis. in part, can be attributed to extremely limited data about the pharmacokinetics and tissue concentrations of cefazolin in pediatric patients. This investigation is the first to determine the serum and tissue concentration at incision, during surgery and at closure in patients undergoing gastrointestinal surgeries. Although substantial interpatient variation occurred, our data showed that the tissue concentrations were maintained above the MIC against the common susceptible pathogens throughout the procedure. Thus. our current practice of using cefazolin as described in this study appears adequate to protect against infection in infants and children undergoing gastrointestinalprocedures. Limited data are available about the pharmacokinetics of cefazolin in children. A study in 8 children with osteomyelitis has reported an elimination half-life of 1.7-1.8 h (5), which is consistent with the values in our patients. Total body clearance and distribution volumes have been reported only in newborn infants; clearance ranged from 0.53-1.1 mlIminlkg and distribution volume from 0.21-0.34 lIkg in these infants (6). A comparison of these data with those of this study suggests that the
52
Eur. J. DrugMetab. Pharmacokinet., 1991, No.1
clearance was higher in our children, perhaps due to the maturation of the kidney, and the distribution volume was higher in newborn infants (age 2-28 days) due to their increased extracellular fluid volume as well as increased free (unbound) fraction of cefazolin in plasma. Although cefazolin was initially marketed in the USA in 1973, little is known about its clinical pharmacology in pediatric patients. This lack of knowledge of phannacokinetics is remarkable as it is widely used in children. The present data validate our current dosing regimen for surgical prophylaxis which seems appropriate and safe. Although cephalosporins generally have a wide margin of safety, specific studies should be done to evaluate the phannacokinetics and tissue concentrations of all antibiotics used for surgical prophylaxis in infants and children to prevent postoperative infections.
REFERENCES 1. Manufacturer's product infonnation for cefazolin (Ancef and K.efzol), Phylliciatt$' Desk Reference, 4300 edn., 1989. Medical Economics Co., Ine., Oradell, NJ pp. 1187-1189, 2037-2039. 2. Lowry D.H., HaWngll A.B. (1942) : Histochemical changes essociated with aging: methods and calculations. J. BioI. Chem., 143,257-264. 3. Dudley N.M, Nightingale C.H., Drezner AD., Low H.B., Quinti1iani R. (1984) : Comparative penetration of cefonicid and cefazolin into the atrial appendage and pericardial fluid of patients undergoing open-heart surgery. Antimicrob. Agents Chemother.,26,347-350. 4. Nelson J.D. (1989-90): Pocketbook of Pediatric Antimicrobial Therapy, 8th edn.. Baltimore, Willill11lll & Wilkins, p. 66. 5. TezlaffT.R., Howard J.B., McCracken G.H., Calderon E., Larronde J. (1978) : Antibiotic concentrations in pus and bone of children with osteomyelitis, J. Pediatr., 92, 135-140. 6. Deguchi Y., Koshida R., Nakashima E., et al. (1988): Interindividual changes in volume of distribution of cefazolin in newborn infants and il$ prediction based on physiological pharmacokinetic concepts, J. Pharm. ScL, 77, 674-678.
