ANTI-INFLAMMATORY/IMMUNOSUPPRESSIVE/ANTIHISTAMINE
Effect of Food on the Pharmacokinetics of Cyclosporine in Healthy Subjects Following Oral and Intravenous Administration Suneel John
G.
K. Gupta,
PhD,
Gambertoglio,
Roberto
PharmD,
I. Tomlanovich,
C. Manfro, MD, Stephen Marvin R. Garovoy, MD,
and
Leslie
MD, Z. Benet,
PhD
The pharmacokinetics of cyclosporine were studied in healthy subjects following administration of cyclosporine both orally (10 mg kg) and intravenously (4 mg kg1) without and with high fat meals. Both blood and plasma samples (separated at 37#{176}C)were analyzed for cyclosporine concentration. Blood and plasma clearances of cyclosporine were calculated to be 0.36 and 0.47 L hr1 Kg, respectively, and volume of distribution at steady state was calculated to be 1.21 L Kg, when cyclosporine was administered without a high fat meal. Using plasma analysis, the oral bioavailability of cyclosporine to be 21 and 79%, when administered When cyclosporine was administered both clearance and volume of distribution clearances of cyclosporine were 0.44 and
was estimated respectively. meal,
plasma cyclosporine only
enhances
was
administered
the
absorption
along
with
of cyclosporine
without
fat also
L hr’ meal.
enhances
with
a high
together
with
We
conclude
yclosporine (CYA) is a potent immunosuppressive agent widely used in preventing organ graft rejection. The pharmacokinetics of CYA are known to be highly variable between and within individuals, following organ transplantation.1 It is also established that the age of a patient and the type of organ being transplanted contribute to this variability.2 Nonspecific analytical techniques for the analysis of CYA in various biological fluids have also accounted for some of the variability observed in initial pharmacokinetic studies. Although the pharmacokinetics of CYA have been extensively investigated in various transplant populations, few studies have been carried out in healthy subjects From the
Departments
of Pharmacy
(Drs.
Gupta,
Gambertoglio
and
Benet), Surgery (Drs. Manfro and Garovoy) and Medicine (Dr. Tomlanovich), University of California, San Francisco, CA 94143. Dr. Gupta’s present address is ALZA Corporation. 950 Page Mill Rd. Palo Alto, CA 94303. This work was supported in part by NIH grant GM 26691. Address for correspondence: Prof. Leslie Z. Benet, Department of Pharmacy, University of California, San Francisco, CA 94143.0446.
J Clin Pharmacol
1990;30:643-653
not
food
and and
meal,
when
that
its clearance
of distribution. The observed variability in clearance, bioavailability, distribution values for cyclosporine across various pharmacokinetic tially accounted by the type of food administered and the sampling analysis.
C
fat
a high fat Blood and
significantly. Kg, respectively,
increased
0.70
a high but
and
intravenously
volume
volume
of
studies can be parmatrix used for
following either oral or intravenous CYA administration.35 In most of these studies whole blood CYA concentrations have been measured. As CYA preferentially binds to red blood cells and its distribution is concentration dependent, the results of such studies are difficult to compare with transplant populations, where the hematocrit is variable and lower than in healthy subjects. Lindhom et al6 studied CYA pharmacokinetics in healthy subjects, using plasma analysis, following two oral doses. These workers reported a two fold intra-individual and three fold inter-individual difference in AUCs for both total and unbound drug. To date there is no published study reporting the pharmacokinetics of CYA in healthy subjects following both oral and intravenous administration. The effect of food on the absorption of CYA has been reported by Keown et al78 and Ptachcinski et al9 who describe contradictory effects. As both these studies were carried out in kidney transplant patients receiving other drugs, the true contribution of food is unclear. Thus the objectives of the present
643
GUPTA
study were: (1) to establish the pharmacokinetics of CYA following oral and intravenous administration using both blood and plasma CYA concentration sample analyses; (2) to describe the absorption characteristics of CYA; and (3) to determine the effect of food on the absorption and disposition of CYA.
METHODS Clinical Eight healthy subjects (4 men ing 55-74 kg and aged 26-32 after giving written informed
and 4 women) weighyears were studied, consent. The study
protocol
University
was
approved
by the
of Califor-
nia San Francisco Committee on Human Research. Based on medical history, physical examination and standard biochemical blood tests, subjects were classified as healthy. Subjects were asked to refrain from drinking any alcoholic beverages during I week before and on the day of CYA administration. The study was carried out in two phases. The initial phase (low fat) consisted of randomized oral and intravenous CYA administrations when subjects received low fat meals. The second phase (high fat), begun 3 months after completion of the first phase, consisted of an oral followed by an intravenous dose of CYA while subjects received high fat meals. During the first phase (low fat), starting 16 hours before the administration of CYA, subjects were given a high carbohydrate, low fat vegetarian meal, and asked to fast until the next morning. Each volunteer received oral or intravenous CYA in a randomized cross-over fashion. Oral CYA, 10 mg kg1, was given as a well dispersed chocolate emulsion. Intravenous CYA, 4 mg kg1, was administered over 2.5 hours as a constant rate infusion using a calibrated AVI 200 infusion pump. When the subjects received the intravenous administrations, they were also given a placebo form of the chocolate oral vehicle at the start of the infusion. During the first 2.5 hours of the study, subjects were allowed only one drink of decaffeinated tea or coffee. After 2.5 hours,
subjects were then given a breakfast consisting of fruits, fruit juices, low fat fruit yogurt, and decaffeinated tea or coffee. A low fat, high carbohydrate lunch, with plenty of fruits and fruit juices was given 6 hours after dosing. After lunch, subjects were allowed nonalcoholic drinks and in the evening, after 11 hours of dosing, a low fat dinner was given. During the second phase (high fat), starting 16 hours before the administration of CYA, subjects were given a high fat vegetarian meal, and asked to fast until the next morning. Each volunteer received
644
#{149} J Clin Pharmacol
1990;30:643.-653
ET
AL
an oral dose nous dose. scribed for
of CYA and 3 months later an intraveBoth doses were administered as dethe low fat phase above, but midway through a high fat breakfast. Six and 11 hours after the dosing a high fat lunch and dinner were given, respectively. Subject 6 was not available for the second intravenous administration. The high fat breakfast consisted of two scrambled eggs with butter, hash brown potatoes, and buttered toast. Lunch and dinner consisted of cheese pasta, french fried potatoes, buttered rolls, and cheese cake. Following oral and intravenous administrations, blood samples (14 mL each) were drawn at 0, 0.25, 0.50, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours from an indwelling cannula inserted in one arm. In the low fat phase, treatments were separated by a 7-day period. Both blood and plasma (separated at 37#{176}C)were analyzed for CYA using our recently
published HPLC method.1#{176} The minimum detection limit of the assay was 30 ng mL. Intra-day and inter-day variabilities lesterol and triglyceride ple were measured Diagnostic, Chicago,
were less than 5%. Total choconcentrations in each samusing the TDx system (Abbott IL). Samples were also analyzed
for immunological response and discussed in a future publication. Data The
these
results
will
be
Analysis total
area
under
the
concentration-time
observed
curve
blood
(AUC)
was
or
plasma
calculated
using the log trapezoidal rule for decreasing plasma concentrations and the linear trapezoidal rule for increasing concentrations following oral dosing. Clearance for each intravenous infusion was calculated by dividing the dose by the corresponding AUC. Using the SIPHAR computer program (Simed, Creteil, France) a two-compartment open model was fitted to both the blood and plasma CYA concentra-
tion-time
data
obtained
following
intravenous
ad-
ministration. The relevant rate constants associated with this model were estimated and used for determination of absorption parameters using the method of Loo and Riegelman.11 Bioavailability (F), mean residence time (MRT), and volume of distribution at steady state (V) were calculated using noncompartmental techniques,12 corrected for duration of infusion. Mean absorption time (MAT) was calculated as AUMC/AUC for oral dosing minus the MRT for intravenous dosing during the same phase. The F-ratio
test was performed models and a level cant. tion.
All
data
to discriminate between the of P < .05 was considered signifi-
presented
are
mean
±
standard
devia-
EFFECT
OF
FOOD
ON
PHABMACOKINETICS
TABLE Subject
Characteristics and Area Under Curves Obtained Following During
OF
CYCLOSPOBINE
I
the Total Cholesterol and Total Triglyceride Concentration Intravenous and Oral Cyclosporine Administrations Both Low and High Fat Phases Low Fa t Phase
.
Subject (No.)
Sex
M M F
1 2
3 4
F M
5
M
6 7 8
F
F
Mean
25 24 28 28
60 73
34
67 75
31 29 30
29 3
SD Chol
Weight (kg)
=
Ar ea under
62 56
High Fat Phase
IV
.
Age (yr)
P0
Chol
Trig
4179
2272 1932 1150 1567 2075 4924
3393 4390 3684 5766
IV
Chol
Trig
3406 3860 4168
Trig
Chol
Trig
2033
4005
3062
7056
3818
3353 3737
3258 1320
3166
2824 2255 2203
5771 4084
4050
2262 1253 1402
6102
2587
1913 6447 1682
3276
3327
-
-
3029
4839 3294 4335
3062
3317
4834 3669 2818
3367 1808
2154
4578
1307
3484 3440 332
2474
3704
1687
2780
4755
2502
478
1446
903
65 55
64
4248
2388
4066
2287
7
718
1160
537
1719
prof lie (mg hr/dL).
RESULTS Individual subject characteristics and integrated lipid concentration measurements for each drug dosing are given in Table I. The CYA blood and plasma concentration-time data obtained following intravenous administration were best described by a two-compartment model. A three-compartment model was found to be unnecessary. Figure I displays the observed blood and plasma concentration-time data obtained during the low fat phase following oral and intravenous administrations in a representative volunteer. The various estimated pharmacokinetic parameters for all subjects during the low fat phase, using both blood and plasma measurements, are listed in Tables II and III, respectively. During analysis of the oral dosing samples of the low fat phase, concentration measurements for standardized controls fell outside our acceptable limits (i.e., C.V. > 5%) for subjects 3 and 5 and insufficient blood volume was available to repeat these analytical measurements. Using plasma data, the mean half-lives associated with the first and second exponential terms were 0.48 and 5.6 hours, and mean V1 and V were 0.61 ± 0.5 and 1.19 ± 0.24 L kg, respectively. The mean CL estimated using the plasma data (0.47 ± 0.10 L hr kg) was significantly (P < .005) higher than that estimated using blood data (0.36 ± 0.06 L hr kg). In contrast, V5. and V1 estimates were not significantly different between blood and plasma measurements. As a result
ANTI-INFLAMMATORY/IMMUNOSUPPRESSIVE/ANTIHISTAMINE
P0
ChoI
4129 4551 3890
the total chole sterol-time
Time
Trig
MRT
was
with
plasma
longer
Absorption
ing
the total
Are a under
=
oral
triglyc eride -time
using
(P
Effect of Food on the Pharmacokinetics of Cyclosporine in Healthy Subjects Following Oral and Intravenous Administration Suneel John
G.
K. Gupta,
PhD,
Gambertoglio,
Roberto
PharmD,
I. Tomlanovich,
C. Manfro, MD, Stephen Marvin R. Garovoy, MD,
and
Leslie
MD, Z. Benet,
PhD
The pharmacokinetics of cyclosporine were studied in healthy subjects following administration of cyclosporine both orally (10 mg kg) and intravenously (4 mg kg1) without and with high fat meals. Both blood and plasma samples (separated at 37#{176}C)were analyzed for cyclosporine concentration. Blood and plasma clearances of cyclosporine were calculated to be 0.36 and 0.47 L hr1 Kg, respectively, and volume of distribution at steady state was calculated to be 1.21 L Kg, when cyclosporine was administered without a high fat meal. Using plasma analysis, the oral bioavailability of cyclosporine to be 21 and 79%, when administered When cyclosporine was administered both clearance and volume of distribution clearances of cyclosporine were 0.44 and
was estimated respectively. meal,
plasma cyclosporine only
enhances
was
administered
the
absorption
along
with
of cyclosporine
without
fat also
L hr’ meal.
enhances
with
a high
together
with
We
conclude
yclosporine (CYA) is a potent immunosuppressive agent widely used in preventing organ graft rejection. The pharmacokinetics of CYA are known to be highly variable between and within individuals, following organ transplantation.1 It is also established that the age of a patient and the type of organ being transplanted contribute to this variability.2 Nonspecific analytical techniques for the analysis of CYA in various biological fluids have also accounted for some of the variability observed in initial pharmacokinetic studies. Although the pharmacokinetics of CYA have been extensively investigated in various transplant populations, few studies have been carried out in healthy subjects From the
Departments
of Pharmacy
(Drs.
Gupta,
Gambertoglio
and
Benet), Surgery (Drs. Manfro and Garovoy) and Medicine (Dr. Tomlanovich), University of California, San Francisco, CA 94143. Dr. Gupta’s present address is ALZA Corporation. 950 Page Mill Rd. Palo Alto, CA 94303. This work was supported in part by NIH grant GM 26691. Address for correspondence: Prof. Leslie Z. Benet, Department of Pharmacy, University of California, San Francisco, CA 94143.0446.
J Clin Pharmacol
1990;30:643-653
not
food
and and
meal,
when
that
its clearance
of distribution. The observed variability in clearance, bioavailability, distribution values for cyclosporine across various pharmacokinetic tially accounted by the type of food administered and the sampling analysis.
C
fat
a high fat Blood and
significantly. Kg, respectively,
increased
0.70
a high but
and
intravenously
volume
volume
of
studies can be parmatrix used for
following either oral or intravenous CYA administration.35 In most of these studies whole blood CYA concentrations have been measured. As CYA preferentially binds to red blood cells and its distribution is concentration dependent, the results of such studies are difficult to compare with transplant populations, where the hematocrit is variable and lower than in healthy subjects. Lindhom et al6 studied CYA pharmacokinetics in healthy subjects, using plasma analysis, following two oral doses. These workers reported a two fold intra-individual and three fold inter-individual difference in AUCs for both total and unbound drug. To date there is no published study reporting the pharmacokinetics of CYA in healthy subjects following both oral and intravenous administration. The effect of food on the absorption of CYA has been reported by Keown et al78 and Ptachcinski et al9 who describe contradictory effects. As both these studies were carried out in kidney transplant patients receiving other drugs, the true contribution of food is unclear. Thus the objectives of the present
643
GUPTA
study were: (1) to establish the pharmacokinetics of CYA following oral and intravenous administration using both blood and plasma CYA concentration sample analyses; (2) to describe the absorption characteristics of CYA; and (3) to determine the effect of food on the absorption and disposition of CYA.
METHODS Clinical Eight healthy subjects (4 men ing 55-74 kg and aged 26-32 after giving written informed
and 4 women) weighyears were studied, consent. The study
protocol
University
was
approved
by the
of Califor-
nia San Francisco Committee on Human Research. Based on medical history, physical examination and standard biochemical blood tests, subjects were classified as healthy. Subjects were asked to refrain from drinking any alcoholic beverages during I week before and on the day of CYA administration. The study was carried out in two phases. The initial phase (low fat) consisted of randomized oral and intravenous CYA administrations when subjects received low fat meals. The second phase (high fat), begun 3 months after completion of the first phase, consisted of an oral followed by an intravenous dose of CYA while subjects received high fat meals. During the first phase (low fat), starting 16 hours before the administration of CYA, subjects were given a high carbohydrate, low fat vegetarian meal, and asked to fast until the next morning. Each volunteer received oral or intravenous CYA in a randomized cross-over fashion. Oral CYA, 10 mg kg1, was given as a well dispersed chocolate emulsion. Intravenous CYA, 4 mg kg1, was administered over 2.5 hours as a constant rate infusion using a calibrated AVI 200 infusion pump. When the subjects received the intravenous administrations, they were also given a placebo form of the chocolate oral vehicle at the start of the infusion. During the first 2.5 hours of the study, subjects were allowed only one drink of decaffeinated tea or coffee. After 2.5 hours,
subjects were then given a breakfast consisting of fruits, fruit juices, low fat fruit yogurt, and decaffeinated tea or coffee. A low fat, high carbohydrate lunch, with plenty of fruits and fruit juices was given 6 hours after dosing. After lunch, subjects were allowed nonalcoholic drinks and in the evening, after 11 hours of dosing, a low fat dinner was given. During the second phase (high fat), starting 16 hours before the administration of CYA, subjects were given a high fat vegetarian meal, and asked to fast until the next morning. Each volunteer received
644
#{149} J Clin Pharmacol
1990;30:643.-653
ET
AL
an oral dose nous dose. scribed for
of CYA and 3 months later an intraveBoth doses were administered as dethe low fat phase above, but midway through a high fat breakfast. Six and 11 hours after the dosing a high fat lunch and dinner were given, respectively. Subject 6 was not available for the second intravenous administration. The high fat breakfast consisted of two scrambled eggs with butter, hash brown potatoes, and buttered toast. Lunch and dinner consisted of cheese pasta, french fried potatoes, buttered rolls, and cheese cake. Following oral and intravenous administrations, blood samples (14 mL each) were drawn at 0, 0.25, 0.50, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours from an indwelling cannula inserted in one arm. In the low fat phase, treatments were separated by a 7-day period. Both blood and plasma (separated at 37#{176}C)were analyzed for CYA using our recently
published HPLC method.1#{176} The minimum detection limit of the assay was 30 ng mL. Intra-day and inter-day variabilities lesterol and triglyceride ple were measured Diagnostic, Chicago,
were less than 5%. Total choconcentrations in each samusing the TDx system (Abbott IL). Samples were also analyzed
for immunological response and discussed in a future publication. Data The
these
results
will
be
Analysis total
area
under
the
concentration-time
observed
curve
blood
(AUC)
was
or
plasma
calculated
using the log trapezoidal rule for decreasing plasma concentrations and the linear trapezoidal rule for increasing concentrations following oral dosing. Clearance for each intravenous infusion was calculated by dividing the dose by the corresponding AUC. Using the SIPHAR computer program (Simed, Creteil, France) a two-compartment open model was fitted to both the blood and plasma CYA concentra-
tion-time
data
obtained
following
intravenous
ad-
ministration. The relevant rate constants associated with this model were estimated and used for determination of absorption parameters using the method of Loo and Riegelman.11 Bioavailability (F), mean residence time (MRT), and volume of distribution at steady state (V) were calculated using noncompartmental techniques,12 corrected for duration of infusion. Mean absorption time (MAT) was calculated as AUMC/AUC for oral dosing minus the MRT for intravenous dosing during the same phase. The F-ratio
test was performed models and a level cant. tion.
All
data
to discriminate between the of P < .05 was considered signifi-
presented
are
mean
±
standard
devia-
EFFECT
OF
FOOD
ON
PHABMACOKINETICS
TABLE Subject
Characteristics and Area Under Curves Obtained Following During
OF
CYCLOSPOBINE
I
the Total Cholesterol and Total Triglyceride Concentration Intravenous and Oral Cyclosporine Administrations Both Low and High Fat Phases Low Fa t Phase
.
Subject (No.)
Sex
M M F
1 2
3 4
F M
5
M
6 7 8
F
F
Mean
25 24 28 28
60 73
34
67 75
31 29 30
29 3
SD Chol
Weight (kg)
=
Ar ea under
62 56
High Fat Phase
IV
.
Age (yr)
P0
Chol
Trig
4179
2272 1932 1150 1567 2075 4924
3393 4390 3684 5766
IV
Chol
Trig
3406 3860 4168
Trig
Chol
Trig
2033
4005
3062
7056
3818
3353 3737
3258 1320
3166
2824 2255 2203
5771 4084
4050
2262 1253 1402
6102
2587
1913 6447 1682
3276
3327
-
-
3029
4839 3294 4335
3062
3317
4834 3669 2818
3367 1808
2154
4578
1307
3484 3440 332
2474
3704
1687
2780
4755
2502
478
1446
903
65 55
64
4248
2388
4066
2287
7
718
1160
537
1719
prof lie (mg hr/dL).
RESULTS Individual subject characteristics and integrated lipid concentration measurements for each drug dosing are given in Table I. The CYA blood and plasma concentration-time data obtained following intravenous administration were best described by a two-compartment model. A three-compartment model was found to be unnecessary. Figure I displays the observed blood and plasma concentration-time data obtained during the low fat phase following oral and intravenous administrations in a representative volunteer. The various estimated pharmacokinetic parameters for all subjects during the low fat phase, using both blood and plasma measurements, are listed in Tables II and III, respectively. During analysis of the oral dosing samples of the low fat phase, concentration measurements for standardized controls fell outside our acceptable limits (i.e., C.V. > 5%) for subjects 3 and 5 and insufficient blood volume was available to repeat these analytical measurements. Using plasma data, the mean half-lives associated with the first and second exponential terms were 0.48 and 5.6 hours, and mean V1 and V were 0.61 ± 0.5 and 1.19 ± 0.24 L kg, respectively. The mean CL estimated using the plasma data (0.47 ± 0.10 L hr kg) was significantly (P < .005) higher than that estimated using blood data (0.36 ± 0.06 L hr kg). In contrast, V5. and V1 estimates were not significantly different between blood and plasma measurements. As a result
ANTI-INFLAMMATORY/IMMUNOSUPPRESSIVE/ANTIHISTAMINE
P0
ChoI
4129 4551 3890
the total chole sterol-time
Time
Trig
MRT
was
with
plasma
longer
Absorption
ing
the total
Are a under
=
oral
triglyc eride -time
using
(P
