`
`PIIARMACOKINETICS/PIIARMACODYNAMICS
`
`Pharmacokinetics of clindamycin HCl administered intravenously,
`
`intramuscularly and subcutaneously to dogs
`
`E. LAVY*
`
`G. ZIV‘r
`
`M. SHEM-TOV;t
`
`A. GLICKMAN§ &
`
`A.DEYfi
`
`*K0ret School Of Veterinary Medicine. The
`Hebrew University of Ierusalem, P.O. Box
`12, Rehovot 76100, Israel, 3;Vetgenerics
`Research G. Ziv Ltd., P.O. Box 2473
`Rehovot 76124, Israel, §Ministry of
`Agriculture, Kimron Veterinary Institute,
`P.O. Box 12, Bet-Dayan 50250, Israel, and
`1lAvind Chemie GmbH, Hannover, Germany.
`Tpassed away November 1997
`
`Lavy, E., Ziv, G., Shem-Tov. M., Glickman, A., Dey, A. Pharmacokinetics of
`clindamycin HCl administered intravenously,
`intramuscularly and subcuta-
`neously to dogs]. vet. Pharmacol. Therap. 22, 261—265.
`
`A buffered aqueous solution of clindamycin Hcl (200 mg/mL) was injected
`intravenously (i.v.) intraniuscularly (i.n1.) and subcutaneously (s.c.) in a non-
`randomized, partial cross-over trial involving six male and six female dogs.
`Blood samples were collected at conventional, predetermined time periods and
`serum drug concentrations were determined by microbiological assay. Dogs
`were observed clinically for signs of pain, and activity of serum creatine
`phosphokinase (CPK) was monitored after i.m. dosing.
`The i.v. data from five of the dogs best fitted a two-compartment open-system
`pharmacokinetic model whereas a non-compartment model was most suitable
`for analysis of the data from the remaining seven dogs. The mean i.v.
`
`elimination half-life (£553) and the mean residence time (MRT) were 124 and
`143 min, respectively. The mean volume of distribution at steady state (VSS) was
`0.86 L/kg. Little pain was recorded upon i.m. injection; mean peak serum drug
`concentration (Cmix) was 4.4 ug/mL, the elimination half-life (ti/261) was 247
`n1in and the calculated bioavailability (F) was 115% of the i.v dose. Serum CPK
`activity was elevated to 25-fold the pretreatment level in samples collected 4, 8
`and 12 h after
`i.m.
`injection. Pain was not
`recorded after
`s.c. drug
`administration: the mean Cmax of 20.8 ug/mL was significantly greater than
`the corresponding value for the i.m. route, and F was 310%. The s.c. route
`appears to be superior to the i.m. route in terms of local tolerance and serum
`drug level; a 10 mg/kg SID treatment regimen is suggested for treatment of
`canine infections due to clindamycin sensitive bacteria.
`
`(Paper received 16 December 1998; accepted for publication 1 1 May 1999)
`
`E. Lavy, Koret School of Veterinary Medicine, The Hebrew University, P.O. Box 12,
`Rehovot 76100, Israel.
`
`INTRODUCTION
`
`A semisynthetic derivative of lincomycin, clindamycin has been
`shown to be clinically effective and is recommended for treatment
`of staphylococcal and anaerobic infections of skin, soft tissue and
`bone in dogs (Berg et al.. 1984: Greene. 1989: Braden et al.. 1988:
`Braden et al., 1987). Clindamycin is available for parenteral
`administration as the 2-phosphate and hydrochloride. Clindamy-
`cin 2-phosphate is microbiologically inactive, but is hydrolized in-
`vivo to clindamycin (1/Vebber et al., 1980). The pharmacokinetics of
`clindamycin phosphate in dogs were studied after single intrave-
`nous (i.v.) and intramuscular (i.m.) administrations at 11 mg/kg
`clindamycin (Webber et al.. 1980) and after single subcutaneous
`(s.c.)
`injections at 2.75, 5.5, 11 and 21 mg/kg clindamycin
`(Webber et al.. 1980). Based on the pharmacokinetics of the drug,
`s.c. dosage regimen of 11 mg/kg of clindamycin free base as
`clindamycin-2-phosphate/kg body weight every 24 h was
`recommended (Budsberg et al., 1992). The i.m. administration of
`clindamycin-2-phosphate solution (50 mg/1nL) induced signs of
`
`this route was not
`therefore,
`pain and other side-effects and,
`recommended (Budsberg et al., 1992). A buffered 20% aqueous
`solution of clindamycin hydrochloride (200 mg/mL) is available
`for pharmacokinetic and clinical testing. The purpose of this study
`was to determine the concentrations of clindamycin in normal
`canine serum after single i.v.,
`i.1n. and s.c. administrations of
`clindamycin HCl and compare the derived kinetic variables with
`those obtained earlier
`in dogs
`injected with equal doses of
`clindamycin phosphate (Webber et al., 1980: Budsberg et al.,
`1 9 9 2). Local tolerance and appearance of side—effects following i.m.
`a11d s.c. administrations were particularly examined.
`
`MATERIALS AND METHODS
`
`Animals
`
`Twelve adult m'Lxed breed dogs, six males and six females (4—13 kg
`b.w.) were used in the study. All dogs were housed in the test
`facility for 3 weeks prior to the study. Dogs had free access to
`
`©1999 Blackwell Science Ltd
`
`261
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`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01325
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`
`
`262 E. Lavy ct al.
`
`water and commercial dry dog ration before and during the study.
`Inclusion criteria included normal findings on physical exa1nina-
`tio11, complete blood count (CBC) serum concentrations of urea
`nitrogen, creatinine, albumin,
`total protein glucose, bilirubin,
`triglycerides, cholesterol, calcium, magnesium, sodium, potas-
`sium, chlorides,inorganic phosphorus and serum activities of
`alkaline phosphataes, alanine aminotransferase, aspartate a1nino—
`transferase and amylase were determined. Dogs selected for the
`study exhibited normal CBC and blood biochemistry test results.
`
`Experimental design
`
`Intravenous protocol
`jugular vein catheters were placed in each dog; patency of each
`catheter was maintained with heparinized saline. A blood sample
`was taken prior to the beginning of the trial. Each dog was given
`the 20% buffered aqueous clindamycin HCl i.v. at 10 mg/kg.
`Blood samples were obtained at 10, 20, 30, 40, 50, 60, 80, 90,
`120. 180, 240, 360, 480 and 600 min post injection. Blood was
`allowed to clot at 20°C for 2 h and was then centrifuged at
`1000 X g; the serum was collected and stored at —20°C until it
`was assayed.
`
`Intramuscular and subcutaneous protocols
`A 2 week rest period was allowed for all dogs. All indwelling
`jugular venous catheter was placed and maintained as for the i.v.
`protocol, and a baseline blood sample was taken. The injection
`site (4 X 4 cm2 area) on the dorsal aspect of the left and right
`sites were then shaved to remove short hair. Nine dogs received a
`single i.m. injection of the 20% clindamycin HCl at 10 mg/kg in
`the left—side of the neck and the remaining three dogs received a
`single i.1n. injection of 3—5 n1L sterile physiological saline iii the
`neck. Two weeks later, nine dogs were prepared by procedures
`identical to those used before i.1n. drug administration. Six dogs
`received a single s.c. injection of 20% clindamycin HCI at 10 mg/
`kg in the right—side of
`the neck. All dogs were observed
`immediately following i.1n. and s.c.
`injections for evidence of
`pain. itching or irritation. The injection sites on both sides of the
`neck were palpated at each blood sampling time and at least two-
`times per day on the following 2 days and any abnormal finding
`such as pain, swelling and discoloration were recorded.
`Blood samples were obtained at 15, 30, 60. 90. 150, 210.
`270. 390, 510, 630, 720 and 1440. min post i.m. injection.
`Blood samples were collected at 30, 45, 60, 90, 120, 180, 240,
`360. 480, 600, 720 and 1440 min post s.c. injection. Blood
`samples were processed as for after i.v. injection.
`
`Clindamycin analysis
`Clindamycin concentrations were measured by microbiological
`well/agar plate diffusion assay as previously described (Bennett at
`al., 1966). The assay organism S.
`lutea ATCC 9341, was
`inoculated into antibiotic Medium No.
`1
`(Difco, Detroit, MI,
`USA) and a 7.0 mm layer seeded medium was added to each Petri
`Plates. Six wells, 8 mm in diameter, were cut into the agar at
`equal distances. A 50.0 uL aliquot of samples (and standard
`clincamycin HCl solution) was alternately added to each well and
`
`the plates were incubated at 3 7°C for 14—16 h. The concentra-
`tion of drug in each sample was calculated from zone of inhibition
`diameters using polinomial regression techniques. Sensitivity
`limit of assay method was 0.1 pg/mL. Standard curves were
`derived using clindamycin HCl (Sigma Chemical Co. St. Louis,
`MO, USA)
`in dog serum. The correlation coefficient of the
`standard curve from 0.10 to 6.0 ug/mL was 0.99 (P< 0.001).
`Samples with concentrations > 6.0 ug/mL were diluted with
`antibiotic-free dog serum to bring clindamycin concentrations
`within the range of the standard curve. The coefficients of
`variation of
`repeatedly assayed samples at concentrations
`ranging between 1 6 ug/mL and 0.1 1.0 ug/mL were 7.5%
`and 12.5%. respectively. Samples were assayed in duplicate and
`data are reported as mean i SD. It was recognized that this assay
`fails to distinguish between clindamycin and its putative active
`metabolites and,
`therefore,
`results were expressed as serum
`clindamycin antimicrobial equivalent activity. Thus the term
`‘clindamycin concentration’ where used throughout this report is
`rather clindamycin antimicrobial equivalent activity.
`
`Serum creatine phosphokinase ( CPK)
`Serum CPK values were determined, using as enzymatic method
`(CK-NAC-active creatine kinase EC2.7.3.2, Randox Laboratories
`Ltd., Crumlin, Northern Ireland), in blood samples collected at 0,
`4, 8, 12, 24, 32, 48 and 72 h after nine dogs were injected i.m.
`with 20% clindamycin HCl solution, three dogs were injected with
`saline, three dogs were injected s.c. with 20% clindamycin HCl
`and three dogs were administered saline s.c. As large differences in
`pretreatment CPK values were found among the dogs examined,
`serum CPK data were converted to percentage by dividing each
`post
`treatment value by the pretreatment value for
`the
`corresponding animal. The post treatment CPK data are presented
`as mean i SD-fold rise from pretreatment (baseline) CPK value.
`
`Data analysis
`Estimates of first—order rate constants and volumes were initially
`obtained by subjecting mean data to analysis. using iterative least
`squares regression analysis
`(Brown & Manno, 1978). The
`concentrations vs. time data from each dog were then analysed,
`using a microcomputer program for nonlinear weighted least
`square regression (Bourne, 1986).
`The most appropriate pharmacokinetic model was selected
`on the basis of the lowest weighted sum of squares and the
`lowest Akaike’s information criterion (AIC) value (Yamaoka et
`al., 1978) for data from each dog. The i.v., i.m. and s.c. areas
`under the curves (AUCs) were calculated using trapezoidal
`approximations between time of drug administration and 1440
`min afterwards. Differential calculus methods
`(Edwards &
`Penney, 1982) were used to estimate peak serum drug
`concentrations (Cmax) and time of Cmax (tmax) after i.m. and
`s.c.
`administrations. Kinetic
`values
`are
`presented
`as
`mean : SD; half lives, however. are presented as harmonic
`mean : pseudo-SD (Lam et al. 1985). The paired Student’s
`t—test was used for calculating the significance of the differences
`in the mean kinetic values for the i.m. and s.c. routes: P < 0.05
`
`value was considered significant.
`
`©1999 Blackwell Science Ltd, ]. vet, Pharmacol. Therap. 22, 261—2 65
`
`Astrazeneca Ex. 2121 p. 2
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`
`RESULTS
`
`Clinical sig11s i11dicative of slight paii1 were noticed in four to five
`of the dogs immediately following i.m. injection: the remaining
`dogs did not exhibit any pain reaction. Signs suggesting pain or
`discomfort were not shown by any dog after s.c.
`injection.
`Palpation of the injection site did not elicit any pain reaction.
`Local changes could not be felt at the injection site. Thus, the
`neck side injected with clindamycin HCI could not be differ-
`entiated from the side injection with sterile saline solution.
`Mean serum clindamycin concentrations after i.v., i.m. and
`s.c. administrations are presented (Table 1). Data are also
`presented graphically as mean log10 serum concentrations vs.
`time plot (Fig. 1). The i.v. data from five of the dogs best fitted a
`two-compartment open system pharmacokinetic whereas a one-
`compartment model was most suitable for analysis of data from
`the remaining seven dogs. Thus, the kinetic values Cp°, A, and
`ma presented (Table 2) represent data from these five dogs: it
`shows a rapid rate of drug distribution from the central to the
`peripheral body compartment. The elimination half-life (tmg) and
`the mean residence time (MRT) were 124.0 i 57.0 min and
`143.0 4; 34.0 min, respectively and the steady state volume of
`distribution (VSS) was 0.86 i 0.35 I./kg. After
`i.m. drug
`administration. the mean Cmax (4.4 i 0.5 ug/mL) was signifi-
`cantly (P < 0.05) lower than the corresponding value for the s.c.
`administration (20.8 i 6.2 ug/mL).
`The mean absorption time (MAT) of clindamycin HCl solution
`injected s.c. was significantly shorter than after i.m. administra-
`tion. The mean [I/281 i.m. value (427.0 i 209.0 min) was not
`significantly different from the mean tn/“,1 for the s.c. route
`(310.2 i 190.4 min) but these values were significantly longer
`than the mean i.v.
`tmg. The mean s.c. AUC was significantly
`larger than the mean i.m. AUC and the resulting calculated
`bioavailability (F) values which were 1.15 and 3.1 for the i.m.
`and s.c. routes, respectively (Table 3).
`Serum CPK activity rose sharply within 8 h after i.m/ injection
`of clindamycin HCI: activity returned to pretreatment level by
`48 h post treatment. A minimal rise in serum CPK activity was
`observed after s.c. clindamycin injection. The i.1n. and s.c.
`administration of saline did not affect serum CPK activity.
`
`DISCUSSION
`
`The clinical manifestations of pain described (Budsberg et al.,
`1992) following i.m. administration of 5% solution of clindamycin
`phosphate to dogs were not seen at all after i.m. injection ofmore
`concentrated (20%) buffered aqueous solution of clindamycin HCl.
`We can only speculate on the causes for these differences in local
`tolerance; they could be due to the type of clindamycin salt, the
`presence of buffer or a four-fold smaller volume injected using the
`20% clindamycin HCl solution. The transient rise in serum CPK
`activity observed after i.m. injection of clindamycin HCl to dogs
`(Fig. 2) indicates some degree of muscle tissue damage at the
`injection site (Steinnes et 111.. 1978). However. a similar or even
`higher and more persistent rise has been documented for a long
`
`©1999 Blackwell Science Ltd, ]. vet. Pharmacol. Therap. 22, 261—265
`
`Mean serum clindamycin concentration in dogs 263
`
`(pg/mL) after
`Table 1. Mean serum clindamycin concentrations
`intravenous, intramuscular and subcutaneous injection of clindamycin
`HCl to dogs at 10 mg/kg body weight
`
`Treatment
`
`Time
`(min)
`
`10
`15
`20
`30
`40
`45
`50
`60
`80
`90
`120
`150
`180
`210
`240
`270
`360
`390
`480
`510
`600
`630
`720
`1440
`
`Intravenous
`n=12
`Mean
`SD
`
`Intramuscular
`n=9
`Mean
`
`SD
`
`Subcutaneous
`n=6
`Mean
`SD
`
`2.3
`
`2.2
`2.3
`2.5
`
`1.8
`1.4
`0.6
`1.3
`0.87
`
`0.7
`
`0.45
`
`0.22
`
`0.10
`
`0.11
`
`13.4
`.\IS
`11.3
`10.2
`8.9
`NS
`7.7
`6.8
`5.7.5
`5.6
`4.1
`NS
`3.0
`NS
`2.1
`NS
`0.82
`\]S
`0.46
`NS
`0.31
`NS
`NS
`NS
`
`NS
`2.6
`NS
`3.6
`NS
`NS
`NS
`4.0
`NS
`4.0
`NS
`3.5
`NS
`3.0
`NS
`2.3
`NS
`1.7
`NS
`1.1
`NS
`0.70
`0.60
`0.30
`
`NS
`NS
`NS
`16.8
`NS
`19.5
`NS
`17.4
`NS
`13.5
`12.6
`NS
`10.7
`NS
`6.9
`NS
`4.6
`NS
`3.3
`NS
`2.7
`NS
`1.7
`0.3
`
`12.8
`
`3.8
`
`6.7
`
`4.1
`4.6
`
`3.2
`
`2.2
`
`1.4
`
`1.8
`
`1.6
`
`1.2
`0.1
`
`0.76
`
`0.90
`
`0.60
`
`0.70
`
`0.50
`
`0.40
`
`0.40
`
`0.40
`
`0.40
`
`0.30
`0.30
`0.10
`
`_._ IV
`
`_._ im
`
`_..- s.c.
`
`(pg/mL)
`Concentration
`
`O 0
`
`“.2690
`
`580
`
`1160
`
`1450
`
`Fig. 1. Serum clindamyci11 concentrations (pg/mL. log 10 scale) after
`intravenous, intramuscular and subcutaneous administration of
`clindamycin HCl to dogs at 10 mg/kg.
`
`list of apprived veterinary injectable products which are very
`commonly used in small and large animal practice without any
`observable pain reactions (Rasmussen, 1980; Svendsen, 1983). A
`better safety evaluation of i.m. clindamycin HCl therapy must wait
`until data from multiple injections are available. The present
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`264 E. Lavy ct al.
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`Table 2. Selected pharmacokinetic values for clindamycin HCl admi11is—
`tered intravenously to 12 dogs at 10 mg/kg
`
`findings clearly indicate that the s.c. route is superior to the i.m.
`route in terms of local tolerance.
`
`Kenetic value 8: unit
`
`Mean
`
`Cp°.1Lg/mL
`A, pg/mL
`B, pg/mL
`t./B0,. min
`t./1,3. min
`MRT, min
`V“, L/kg
`V53, L/kg
`AUC, pg/mL.min
`Clt, mL/min/kg
`1-2
`
`18.75
`11.06
`7.54
`11.00
`124.00
`143.00
`0.56
`0.86
`1457.00
`6.10
`0.967
`
`SD
`
`3.71
`3.35
`3.35
`13.30
`57.00
`34.00
`0.11
`0.35
`280.00
`1.10
`0.031
`
`A = ordinal intercept of fastest disposition slope minus the intercept of the
`slowest disposition slope; B= ordinal intercept of the slowest disposition
`slope: Cp° = initial serum concentration; t./1,, = distribution half—life;
`t./2,3.
`elimination half»life; MRT— mean residence time; VC— volume of the
`central compartment; VS5= volume of distribution at steady state;
`AUC: area under the concentratio11—ti111e cutve froi11 zero to 24 11 post-
`treatment; Cl,=tota1 body clearance;
`r2 =correlation coefficient to the
`line of best fit for a two—compartment open system pharmacokinetic.
`
`Table 3. Selected pharmacokinetic values for clindamycin administered
`intramuscularly and subcutaneously to dogs at 10 mg/kg
`Treatment
`
`Kinetic
`value
`and unit
`
`Cmax‘ pg/mL
`tmaxy min
`MAT, min
`tn/131, min
`MRT, min
`AUC, pg/1nL min
`F(‘”')
`
`Intramuscular
`n= 9
`
`Mean
`
`SD
`
`4.4
`73.0
`546.0
`427.0
`700.0
`1806.0
`1.15
`
`0.5
`16.0
`226.0
`209.0
`246.0
`346.0
`0.19
`
`Subcutaneous
`n = 6
`
`Mean
`
`SD
`
`20.8
`46.7
`224.5
`3 10.2
`364.2
`5258.0
`3.10
`
`6.2
`20.1
`163.5
`190.4
`147.3
`2161.0
`0.22
`
`time to peak serum
`Cm”, peak maximal serum concentration; Lmax,
`concentration; MAT=mean absorption time, calculated as MRT,,0,,_,_,,A
`MRTLV; F*=bioavailability, calculated as AUC,,0,,_,_,.A/'AUC,AVA
`
`-~»+-~ Cl§FldEl.~'l'L
`
`we-‘y~ Saline i.m.
`
`Interpretation of data gathered in the course of the present
`study must
`take into consideration the assay method used
`(microbiological). Although a good agreement was shown
`between microbiological and chemical (GC) test results in dog
`serum for clindamycin (Ziv & Shem—Tov, unpublished data), there
`is a slight chance that there are some putative active metabolites.
`The disposition curves after i.v. administration of clindamycin
`11Cl was best represented as a two-compartinent open model in
`only five of the dogs. The i.v study protocol we used called for
`collecting the first post treatment blood sample at 10 min.
`Because of the rapid distribution rate of the drug in the dog
`[ta/,0, of 3.5 i 1.1 min) according to (Budsberg et111., 1992), we
`probably missed observing the distribution phase. Values for the
`other major kinetic parameters found in the present study were
`also different from the values calculated in dogs injected i.v. with
`clindamycin phosphate (Budsberg et111.. 1992). Thus, mean tmg,
`MRT and AUC after clindamycin phosphate administration were
`194.6 min, 263.4 min and 2009.5 pg-n1L, respectively. Such
`differences in kinetic values, although small, could result from
`the rate of appearance of bioactive antibiotic in the serum after
`i.v. administration of the microbiologically inactive clindamycin
`phosphate, differences in body—weight (clindamycin phosphate
`was injected to dogs weighting 20 to 30 kg), (Budsberg ct 111.,
`1992) or slightly different methods used for calculating the
`kinetic variable. On the other hand, mean Clt, VC, and VSS for
`clindamycin phosphate were very close to the corresponding
`values for clindamycin HC1 estimated in the present study.
`Regardless of these small differences, the large VSS of clindamycin
`indicates possible wide distribution in the body fluids and tissues.
`Direct nieasureinents of tissue clindaniycin concentrations in
`humans (Panzer et £11., 1972; Dhawan & Thadepalli, 1982) and
`cats (Brown at 111., 1990) confirmed these assumptions.
`The kinetic variables calculates from the i.m. serum drug level
`data for clindamycin HCl and clindamycin phosphate were in
`good agreement. The short tmax |’_1h) and average bioavailability
`of nearly 100% support rapid and complete absorption of the
`drug from the site of i.m.
`injection, as was remarked earlier
`[Budsberg ct 111., 1992). The kinetic profile of the drug in serum of
`all dogs after s.c administration of clindamycin HCl
`is rather
`unique; mean Cmax (20.8 ug/mL) was nearly 4.5 times greater
`than the mean i.1n. Cmax. Moreover, mean serum concentrations
`during the first 12 h post treatment by the s.c. route were two to
`three-fold higher than the concentrations found after i.m. drug
`administration (Fig. 1). After a nearly equivalent dose of the drug
`(11 mg/kg) was injected s.c. to dogs as clindamycin phosphate
`[Vi/ebber at 111., 1980) a mean Cmax of 6.1 i 0.3 ug/ml. was
`recorded at
`tmax of 40—60 min. We found that the terminal
`elimination rate of
`the drug from serum [ta/,e1) after
`s.c.
`administration of 20% clindamycin HC1 solution (310.2 1
`190.4 min) was considerably longer than the reported [Budsberg
`et 111.. 1992) ti/291 of 234.8 1 27.3 min after an equivalent dose
`was given to dogs i.m. as clindamycin phosphate. A t-/261 of 13.9 h
`was calculated (Webber et111.. 1980) from the serum clindamycin
`data of dogs injected s.c. with clindamycin phosphate.
`
`©1999 Blackwell Science Ltd, ]. vet, Pharmacol. Therap. 22, 261—2 65
`
`Astrazeneca Ex. 2121 p. 4
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`3 & 3
`
`
`
`
`
`
`
`3
`
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`60
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`
`Fig. 2. Serum CPK activity in dogs after intramuscular administration of
`clindamycin HCl at 10 mg/kg.
`
`
`
`It appears therefore. that s.c. administration of clindamycin
`HCl allows for rapid, complete drug absorption and, at the same
`time, acts as a depot wl1ich li111its the rate of drug elin1inatio11
`from serum. A entero-hepatic circulation effect was suggested to
`operate in dogs treated orally with clindamycin HCl (Lavy ct al.,
`1999) contributing to the prolongation of ti/291 to nearly 6 h, and
`for calculated oral bioavailability values exceeding 100%.
`Whatever the pharmacokinetic processes involved.
`it appears
`from the present study that the s.c. route is superior to the i.m. in
`practical terms by permitting a longer treatment interval.
`Earlier studies (Braden et al., 1987; Budsberg et al., 1992)
`attempted to establish i.v. and i.m. dosing recommendations
`using average serum concentrations at steady state with the
`accompanying peak (Cpmax) and through (Cpmax) concentrations
`as means for calculating (Gibaldi, 1982; Riviere, 1988) dosage
`regimens for clindamycin phosphate in dogs. The calculated
`dosage schedule was eventually found to be in agreement with
`the currently recommended oral dosage schedule of 1 1 mg/kg, q
`12 h (Budsberg et al., 1992). We have tried to use a similar
`approach for selecting desirable, potentially antibacterial effec-
`tive, serum drug concentrations in dogs given clindamycin HCI
`by s.c. route. In relating the minimal inhibitory concentration
`(MIC) of clindamycin to its pharmacokinetic properties it has
`been assumed (V4/ebber et al., 1980; Budsberg et al., 1992;
`Brown et al., 1990: Riviere. 1988)
`that:
`(a)
`tissue drug
`concentration at least equal to the MIC is maintained through-
`out the entire dose interval; (b) the drug is minimally bound to
`serum protein and serum concentrations are equal to, or even
`slightly lower than, the concentration in major target sites of the
`body (excluding bone):
`(c)
`the kinetic profiles of the drug in
`serum and the target tissue on multiple dosing are very similar;
`a11d (d)
`the MIC for Staphylococcus aureus/intermedius ranges
`from 0.04 to 0.4 ng/mL and for most anaerobic bacteria, the
`MIC ranges from 0.1 to 3.1 ng/mL but the MIC 90 is in effect
`> 1.6 jig/ml. (Greene, 1989; Budsberg et al., 1992; Brown et al.,
`1990). Using the mean serum concentration values, we observed
`that a single s.c. 10 mg/kg SID dosage regimen appears to be
`appropriate for clindamycin HCl for the treatment of staphylo-
`coccal soft tissue infections. For anaerobic infections, however,
`this treatment should be given BID. A more intensive course of
`clindamycin therapy is apparently required for the treatment of
`staphylococcal bone infections in the dog (Braden et al., 1987:
`Braden et al., 1988; Budsberg et al., 1991).
`
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