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DOSE OPTIMIZATION AND PHARMACOKINETIC/PHARMACODYNAMIC INTEGRATION OF AMOXICILLIN IN LOHI SHEEP (Ovis aries) AND BEETAL GOATS (Capra hircus).

Byline: M. A. Abid, Z. Manzoor, U. Naz and M. M. Ashraf

ABSTRACT

The present study aimed to investigate the interspecies variations in relation to pharmacokinetic profile and optimal dosage regimen of amoxicillin in Lohi sheep and Beetal goats. For this purpose, 16 healthy, adult animals, 8 from each species of Lohi sheep were selected. The animals were 1-2 years of age and 35-45 kg body weight. Amoxicillin was injected as a single intramuscular dose of 15 mg/kg body weight to each animal. Blood samples were collected at specific time intervals over 24 hrs. Plasma drug concentrations and time data was calculated by WinNonlin A(r) for the estimation of pharmacokinetic parameters. Optimal dosage of amoxicillin was also calculated in bot h species. The elimination half-life and mean residence time were higher (P < 0.05) in Beetal goats than Lohi sheep indicating the slow elimination of the drug in Beetal goats.

A priming dose of amoxicillin of 21.6 +- 24.4 mg/kg body weight was suggested with a maintenance dose of 15.7 +- 18.9 mg/kg likely to be repeated every 24 hours in order to provide successful treatment against bacteria with susceptibility of minimum inhibitory concentration (MIC < 1.6 ug/mL) in Lohi sheep and Beetal goats respectively.

Keywords: Amoxicillin, Lohi sheep, Beetal goats, Pharmacokinetics, Dosage regimen.

INTRODUCTION

Antibiotics play a significant role to combat various bacterial infections in livestock sector. Amoxicillin is one of the commonly prescribed antibiotics in humans and animals as well. It is semi-synthetic penicillin belongs to the beta-lactam group of antibiotics and have good affinity to penicillin-sensitive gram-positive and gram-negative bacteria (Plumb, 2005). The action of amoxicillin is bactericidal in nature. It interferes with the bacterial cell wall synthesis and inhibits the enzyme (DD-transpeptidases) which is responsible for the transpeptidation reaction; a vital step to maintain the integrity of cell wall (Chowdhury and Lieberman, 1999). Because of this enzyme inhibition, bacterial cell wall becomes fragile which ultimately leads to the bacterial death. Amoxicillin has great potential against respiratory as well as urinary tract pathogens such as Streptococcus pneumonia, Pasteurella multocida, Escherichia coli and Haemophilus influenza (File et al., 2004; Hernandez et al., 2005).

The binding affinity of amoxicillin to plasma protein is very low. Hence, the major fraction of the drug is widely distributed in the body and penetrates to the different organs and tissues. But it fails to cross the blood brain barrier except in case of meningitis (Abad et al., 2003). Amoxicillin is mainly metabolized in the liver where its two metabolites (amoxicilloic acid and diketopiperazine) are formed (Elsheikh et al., 1999). These are the same metabolites in sheep and goats as reported by Reyns et al. (2008) in pigs. The pharmacokinetic profile of a drug varies with a change in the environment and topography. A number of studies provide some evidences that the pharmacokinetic behavior and dosage regimen of investigated drug were different under local conditions when compared to the foreign documented data in the same animal species (Munawar et al., 2017; Manzoor et al., 2017; Manzoor and Iqbal, 2016; Javed et al., 2006, 2009).

That's why pharmacokinetic study of a drug should be conducted under different environmental conditions in order to optimize proper dosing schedule in each species. In addition, the emergence of bacterial resistance is another alarming issue since the last few years which results due to indiscriminate and improper use of antibiotics or genetics (Gouvea et al., 2015). Hence, it is necessary to use the antibiotic drug only when it is required. Further, the proper dosage regimen of all antibiotics in each animal species should also be strictly followed during the course of treatment. The pharmacokinetic behavior of amoxicillin has been previously studied in different foreign species such as sheep (Delis et al., 2009), goats (Craigmill et al., 1992), llamas (Kreil et al., 2012), buffalo calves (Rasheed et al., 2013) and pigs (Agerso et al., 2000). But there is a lack of pharmacokinetic data in local caprine species.

Therefore, the present study is planned to evaluate the pharmacokinetic profile of amoxicillin in local breeds of sheep and goats in order to predict the proper dosage regimen of amoxicillin in these species.

MATERIALS AND METHODS

Experimental animals and drug administration: A total number of sixteen healthy, adult, non-lactating, female animals were selected, 8 from each species of local breed of sheep (Lohi) and goats (Beetal), weighting between 35-45 kg and 1-2 years of age in both species. All the animals were examined clinically for any symptoms of disease prior to the experiment. Each animal was housed in a separate pen provided with wire mesh to restrict any social contact. All the animals had free access to the drinking water at all the time and were offered seasonal fodder. Special care of each animal was taken by a veterinarian and national guidelines for animal care were strictly followed. The study protocol was reviewed and approved by the Institutional Ethics Committee (IEC) vide notification no. IPPP/UAF/1245-14 dated 05 April 2014.

A commercial preparation of amoxicillin (Trioxyl, 15%) was procured from UnivetA(r) Pvt. Ltd. Poland. For the collection of blood samples one of the jugular vein was cannulated under aseptic conditions with plastic cannula No. 90 (Protex Ltd., England). Prior to drug administration, a control blood sample was collected from each experimental animal. Amoxicillin was then injected as a single intramuscular dose of 15mg/kg body weight to each animal (Rasheed et al., 2013). 1 mL of blood was drawn at 0.5, 1.0, 2.0, 3, 4, 6, 8, 12, 18 and 24 hours post drug administration in heparinized plastic tubes (Kreil et al., 2012). These samples were centrifuged at 4000 rpm for 15 minutes. Plasma was separated from these samples and subjected to analysis.

Pharmacokinetic parameters: The obtained data of plasma concentrations at different time intervals were subjected to a computer program WinNonlinA(r) (Pharsight, version 4.6, USA). Data were analyzed by non-compartmental and compartmental analysis. Minimum Akaike Information Criteria was compared to determine the best fit model among these animals.

In vitro and Ex vivo bacterial killing curves of amoxicillin: The isolate of M. haemolytica WOO221 was grown freshly from beads already stored at -70AdegC on TSA. Ten to twelve bacterial colonies were used to inoculate 9mL of MHB. The culture was allowed to grow overnight at 35AdegC. Multiple of MIC (0.25-8 times) were used to determine the in vitro time-kill curves in Lohi sheep and Beetal goats. Serum samples collected at 1, 2, 4, 6, 8, 10, 12 and 24 hours after i.m. administration of amoxicillin were used to determine the ex vivo bacterial killing curves in Lohi sheep and Beetal goats according to the method previously described by Aliabadi and Lees (2002). The limit of detection was 10 cfu/mL in both experiments.

Pharmacokinetic-Pharmacodynamic integration: From the in vivo PK parameters and in vitro MIC values, the surrogate marker (AUC/MIC) was determined according to the method determined by Sidhu et al. (2010) AUC24/MIC ex vivo data were modeled to the following Sigmoid Emax equation to quantify the three levels of antimicrobial efficacy of amoxicillin i.e. bacteriostatic level (E = 0, no change in bacterial count after 24 hour of incubation), bactericidal (AUC24/MIC = - 3, a 3-log or 99.9% reduction in the original inoculums bacterial count after 24 hour incubation), eradication (AUC24/MIC = -4, a 4-log reduction in bacterial count of original inoculums).

E = E0 + Emax x CNe/EC50 + Ce

Where, E0 denotes a change in log10 cfu/mL of sample post incubation (24 hour) in the control sample (without amoxicillin) compared with the initial inoculum log10 cfu/mL, Emax represents the maximum antibacterial effect determined as difference in log10 cfu/mL in samples incubated with amoxicillin between time 0 and 24 hour when the detection limit (10 cfu/mL) is reached, Ce denotes the AUC24/MIC in the effect compartment (ex vivo site), EC50 is the AUC24/MIC value producing a 50% reduction in bacterial count from the initial log10 cfu/mL, and N is the Hill-coefficient that describes the steepness of the AUC24/MIC curve-effect curve. These PD parameters were calculated using the nonlinear WinNonlinA(r) regression program (Pharsight Corporation).

Determination of drug concentration: The concentration of amoxicillin in plasma was determined by Reversed-Phase High Performance Liquid Chromatography (RP-HPLC) method previously described by Rasheed et al. (2013).

Dosage regimens: Based on the kinetic parameters, the optimal dosage regimen of amoxicillin was calculated in adult healthy Lohi sheep and Beetal goats. The calculation of priming and maintenance dose of amoxicillin after intramuscular administration were based on minimum inhibitory concentration (MIC) of amoxicillin in blood. The MICs of 0.1, 0.4, 0.8, 1.2, 1.6 and 2 ug/mL has been used in the current study for the calculation of dosage regimens of amoxicillin at 12, 24 and 48 hours time intervals in Lohi sheep and Beetal goats. The priming and maintenance doses of amoxicillin were determined by the following equations as described by Baggot (1997).

Maintenance dose (D') = CAdegP(min). Vd (esst-1)

Where, CAdegP (min) = Minimum effective concentration, Vd = Volume of distribution, e=exponantional term, [beta] = over all elimination rate constant, t = Time at which dose was calculated.

The priming dose was obtained by omitting-1 from the above equation:

Priming dose (D) = CAdegP(min). Vd (e sst)

Statistical analysis: Mean with standard deviation values for each parameter was calculated by Microsoft Excel version 2007. Two tailed Student's T test was used to compare the pharmacokinetic parameters in Lohi sheep and Beetal goats. P < 0.05 was considered as significant.

Table 1. Pharmacokinetic parameters of amoxicillin after single intramuscular administration at a dose of 15mg/kg body weight in Lohi sheep and Beetal goats (n = 8).

Parameters###Unit###Lohi sheep###Beetal goats

Cmax###(ug/mL)###3.13+-0.24NS###3.43+-0.12NS

Tmax###(h)###4.24+-0.10 NS###4.15+-0.53 NS

Kabs###(h-1)###0.35+-0.03 NS###0.48+-0.06 NS

T1/2abs###(h)###0.77+-0.02NS###0.69+-0.04NS

Vc###(L/kg)###2.56+-0.21NS###2.90+-0.14NS

Kel###(h-1)###0.14+-0.04NS###0.10+-0.06NS

T1/2 el###(h)###4.73+-0.93*###6.91+-1.24*

ClB###(L/h/kg)###0.37+-0.12NS###0.29+-0.14NS

AUC###(ug.h/mL)###19.9+-1.47NS###21.47+-1.97NS

MRT###(h)###6.83+-1.07*###9.89+-0.86*

Table 2. Dosage regimen of amoxicillin at 12, 24 and 48 hours in Lohi sheep and Beetal goats.

Dosing interval(hours)###12###24###48

###Cop(min) ug/mL###0.1###0.5###1.0###1.3###1.6###2###0.1###0.5###1.0###1.3###1.6###2###0.1###0.5###1.0###1.3###1.6###2

D###Sheep###0.71###2.83###5.66###8.49###11.3###14.2###1.35###5.41###10.8###16.2###21.6###27.1###4.94###19.8###39.5###59.3###79.1###98.8

D'###Sheep###0.34###1.35###2.74###4.18###5.42###6.85###0.98###3.93###7.9###11.8###15.7###19.6###4.6###18.2###36.6###54.8###73.1###91.4

D###Goats###1.57###3.63###7.41###9.79###14.01###17.45###2.71###6.98###13.43###18.56###24.49###29.89###6.65###22.44###43.41###62.99###83.67###99.13

D'###Goats###0.82###3.23###5.34###6.88###9.01###10.92###2.22###6.54###9.76###14.95###18.93###23.42###5.78###19.42###38.86###56.88###77.22###95.88

Table 3. PK/PD integration of ex vivo serum data (mean+-SEM, n = 8) after intramuscular administration of amoxicillin at a dose of 15 mg/kg body weight in Lohi sheep and Beetal goats.

Parameter###Lohi Sheep###Beetal Goats

###Mean###SEM###Mean###SEM

Log E0 (cfu/mL)###-5.04###0.65###-4.95###0.45

Log Emax (cfu/mL)###1.55###0.28###1.78###0.33

Log Emax - Log E0 (cfu/mL)###6.59###1.02###6.73###0.81

EI50###9.48###1.18###8.78###1.08

AUC24h/MIC for bacteriostatic action (h)###37###8###41###9

AUC24h/MIC for bactericidal action (h)###71###13###79###12

AUC24h/MIC for bacterial elimination (h)###86###11###92###10

Slope (n)###6.31###0.98###6.47###0.77

RESULTS

Pharmacokinetic: Data were best fitted by one compartmental model in each animal of both species. The (mean+-SD) plasma values of amoxicillin at different time intervals in both species are presented in Figure 1. The pharmacokinetic parameters of amoxicillin following single intramuscular administration at dose of 15 mg/kg in Lohi sheep and Beetal goats are depicted in Table 1. After intramuscular administration, drug was absorbed from the site of administration to the systemic circulation with T1/2abs values of 0.77 and 0.69 hours in Lohi sheep and Beetal goats respectively. The difference between the absorption half-life was insignificant among both species. Drug reached its maximum concentration as 3.13+-0.24 and 3.43+-0.12 ug/mL at Tmax of 4.24+-0.10 and 4.15+-0.53 hours in Lohi sheep and Beetal goats respectively. There was an insignificant difference for these values in both species.

After achieving the maximum concentration in plasma, amoxicillin was decreased gradually with a constant rate of Kel = 0.14+-0.04 hour in Lohi sheep and Kel = 0.10+-0.06 hours in Beetal goats. The elimination half-life was observed to be 4.73+-0.93 hour in Lohi sheep and 6.91+-1.24 hour in Beetal goats. Amoxicillin was slowly eliminated (P <0.05) in Beetal goats and remained in the body for a longer period of time as indicated by their respective MRT values when compared to Lohi sheep. The total body clearance was 0.37+-0.12 L/h/kg in Lohi sheep and 0.29+-0.14 L/h/kg in Beetal goats.

In vitro bacterial killing of amoxicillin: The in vitro antibacterial activity of amoxicillin is shown in Lohi sheep (Figure 2) and in Beetal goats (Figure 3). A concentration dependent activity of amoxicillin was observed in both species. In Lohi sheep, the initial bacterial count ranged from 6.1-6.3 cfu/mL. At MIC of 2 mg/mL the bacterial count reduced to 5.8 cfu/mL after 2 hours of incubation time. At MIC of 8 mg/mL, the maximum antibacterial activity was observed and bacterial count reduced to 2 cfu/mL after 12 hour incubation period. A similar in vitro antibacterial pattern of amoxicillin was observed in Beetal goats and there was no statistical difference between these data.

Ex vivo antibacterial activity of amoxicillin: The ex vivo bacterial killing of amoxicillin in serum against M. haemolytica WOO221 are shown in Lohi sheep (Figure 4) and in Beetal goats (Figure 5). Samples collected at 6 hours post drug administration decreased bacterial growth to MIC when the antibiotic is time dependent, AUIC (AUC/MIC) and Cmax/MIC when antibiotic is concentration dependent. Recently, Nielsen and Friberg (2013) proposed that the surrogate marker (AUC/MIC) is the better predictor of antibacterial activity of [beta]-lactams antibiotics. White et al. (2004) determined the MIC50 of amoxicillin of 0.125 ug/mL for the majority of the bacterial pathogens. It is reported that the value of AUC/MIC >125 hour provide optimal efficacy against most pathogens (Brown, 1996). To calculate AUIC in the current study, the MIC50 of 0.125 ug/mL has been used for amoxicillin against most of the pathogenic bacteria. The obtained AUIC values were 160 and 172 hour in Lohi sheep and Beetal goats respectively.

So, it is speculated that the current dose (15 mg/kg) of amoxicillin is sufficient to kill most of the bacteria in sheep and goats. But the optimal dosage is that amount of drug which rapidly kills the microorganisms and prevents the regrowth of bacteria without any support of the defensive system of the body (Toutain et al., 2002), So, MIC90 should be used in order to calculate the optimal dosage regimen of an antibiotic. Veloo et al. (2012) suggested the MIC90 of amoxicillin to be 1.5 ug/mL for majority of the bacterial pathogens. By incorporating (MIC90 = 1.5ug/mL) of amoxicillin, the determined values of AUIC were 13.2 and 14.3 hours in Lohi sheep and Beetal goats respectively. The values of the surrogate marker obtained by PK-PD integration in the present study fall below of suggestive values (AUIC = 125 hours). Hence, it is supposed that the current dose of 15 mg/kg will promote the resistant mutants in Lohi sheep and Beetal goats.

The priming dose of amoxicillin by means of pharmacokinetic parameters obtained in this study for the treatment of diseases caused by susceptible bacteria with MIC90 of a$?1.6 ug/mL computed after intramuscular administration at 24 hour interval is 21.6 and 24.4 mg/kg body weight with a maintenance dose of 15.7 and 18.9 mg/kg body weight in Lohi sheep and Beetal goats. It is speculated that these dosage regimens might achieve the desired value of AUIC = 125 hours; predictor of antibacterial activity. Further, the plasma concentrations will remain in mutant prevention window as a minimum for 75% of dosage time interval which is essential [beta]-lactams to ensure the bacteriological eradication and emergence of resistance explained by Drlica (2003).

However, further detailed pharmacodynamic studies of amoxicillin in Lohi sheep and Beetal goats are required to identify an actual as opposed to an assumed MIC90 for confirming the dose by generating sufficient data from field isolates in future studies before issuing final recommendations. Based on the findings of the present study it was concluded that the current administered dose of 15 mg/kg body weight by the intramuscular administration seemed to be effective against most of the respiratory pathogens in Lohi sheep and Beetal goats. However, in the light of PK/PD integration, the optimal doses were suggested to be 21.6 and 24.4 mg/kg/24 hours as priming dose and 15.7 and 18.9 mg/kg/24 hours as maintenance dose which might be successful for therapeutic outcome and prevention of mutant selection pressure in Lohi sheep and Beetal goats respectively.

It is prudent to conduct further detailed pharmacodynamic studies of amoxicillin against enteric disease causing organisms in Lohi sheep and Beetal goats in order to establish PK-PD inter-relationships.

Acknowledgments: The study was funded by Higher Education Commission (HEC), Pakistan.

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