Integration of pharmacokinetic–pharmacodynamic for dose optimization of doxycycline against<i>Haemophilus parasuis</i>in pigs

Zhang, Lili; Li, Y.; Wang, Y.; Sajid, Abdul; Ahmed, Saeed; Li, X.

doi:10.1111/jvp.12512

Cited by 15 publications

(20 citation statements)

References 34 publications

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“…This PK/PD model reflects the relationship between the drug, bacteria, and quantification of the activity (as well as the likely efficacy) of antimicrobial agents against target pathogens (Zhang et al, 2018a). The dynamic model that we used provided a continuous flow of doxycycline to simulate the PK of doxycycline in pigs.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Integration of Doxycycline Against Mycoplasma hyopneumoniae in an In Vitro Model

Zhang

Mao

et al. 2019

Front. Pharmacol.

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Doxycycline is a broad-spectrum antibacterial drug. It is used widely to treat diseases caused by Mycoplasma species. We investigated the antibacterial activity of doxycycline against the Mycoplasma hyopneumoniae strain ATCC25934. The minimum inhibitory concentration (MIC) of doxycycline against M. hyopneumoniae determined by a microdilution method was 0.125 μg/ml. Static time–kill curves with constant drug concentrations (0–64 MIC) showed that a bacteriostatic effect occurred if the doxycycline concentration reached 4 MIC. Doxycycline produced a maximum antimycoplasmal effect (reduction of 2.76 log10CFU/ml) at 64 MIC within 48 h. The effect of doxycycline against M. hyopneumoniae was analyzed by a sigmoid E max model, and there was high correlation between the kill rate and doxycycline concentration (R 2 = 0.986). A one-compartment open model with first-order absorption was adopted and was used to simulate doxycycline pharmacokinetics in porcine plasma. The dynamic time–concentration curve showed that the area under the curve at 24 h (AUC24 h) and C max (peak concentration) after each drug administration was 1.78–48.4 μg h/ml and 0.16–3.41 μg/ml, respectively. The reduction of M. hyopneumoniae (log10CFU/ml) for 1, 2.5, 5, 7.5, 10, 15, 20, and 30 mg/kg body weight was 0.16, 1.29, 1.75, 2.94, 3.35, 3.91, 4.35, and 5.77, respectively, during the entire experiment, respectively. When the dose was >10 mg/kg body weight, continuous administration for 3 days could achieve a bactericidal effect. The correlation coefficient of AUC24 h/MIC, C max/MIC, and %T > MIC (the cumulative percentage of time over a 24-h period that the drug concentration exceeds the MIC) with antibacterial effect was 0.917, 0.923, and 0.823, respectively. Doxycycline showed concentration-dependent activity, and the value of AUC24 h/MIC and C max/MIC required to produce a drop of 1 log10CFU/ml was 164 h and 9.89, respectively.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Integration of Doxycycline Against Mycoplasma hyopneumoniae in an In Vitro Model

Zhang

Mao

et al. 2019

Front. Pharmacol.

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“…For bacteria with the MIC value of 0.4 and 1.5 µg/mL, the T>MIC ratios of doxycycline administered at a dose of 20 mg/kg and a dose interval of 24 h were 152% and 54%, respectively. The AUC 0–24 /MIC ratios to achieve the bacteriostatic and bactericidal effect of doxycycline against Haemophilus parasuis in pigs have been determined as 59 and 98, respectively [ 32 ]. In the present study, an AUC 0–24 /MIC ratio of 100.75 for bacteria with the MIC value of 0.4 µg/mL was higher than that previously reported for optimum bacteriostatic and bactericidal activity [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…The AUC 0–24 /MIC ratios to achieve the bacteriostatic and bactericidal effect of doxycycline against Haemophilus parasuis in pigs have been determined as 59 and 98, respectively [ 32 ]. In the present study, an AUC 0–24 /MIC ratio of 100.75 for bacteria with the MIC value of 0.4 µg/mL was higher than that previously reported for optimum bacteriostatic and bactericidal activity [ 32 ]. In goats, a 20 mg/kg oral dose of doxyxycline can provide the efficient treatment of infections caused by susceptible bacteria with the MIC value of ≤0.4 µg/mL.…”

Section: Discussionmentioning

confidence: 99%

Effects of Single and Repeated Doses on Disposition and Kinetics of Doxycycline Hyclate in Goats

Türk

Çorum

Tekeli

et al. 2020

Animals

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The aims of this study in goats were to determine the pharmacokinetics of doxycycline hyclate following single intravenous (IV), intramuscular (IM) and oral administrations of 20 mg/kg and to evaluate the pharmacokinetics and accumulation of doxycycline hyclate after repeated oral administrations at a 20 mg/kg dose every 24 h for 5 days. Six healthy male goats were used for the study. The study was performed in four periods according to a longitudinal study with a 15-day washout period. Plasma concentrations of doxycycline were determined using HPLC-UV and analyzed by a non-compartmental method. IM injection of doxycycline caused swelling and pain due to irritation in the injection site. After IM and oral administrations, terminal elimination half-life (t1/2λz) and mean residence time (MRT) were prolonged and areas under the curve (AUCs) were low. The mean bioavailability of IM and oral administration was 51.51% and 31.39%, respectively. Following repeated oral administration, the accumulation ratio of doxycycline was 1.76. Pharmacokinetic properties including weak accumulation, wide distribution volume and long elimination half-life can make doxycycline hyclate valuable for repeated use via an oral route in the treatment of some infectious diseases in goats. However, the determination of pharmacodynamic effects on susceptible pathogens isolated from goats is also necessary to confirm the drug dosage regimen.

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“…Numerous PK studies of DC have been conducted in chickens (6), ducks (7), pigs (8), sheep (9), and goats (10). Few studies have been implemented in fish, such as tilapia (11) and grass carp (12,13).…”

Section: Introductionmentioning

confidence: 99%

The Pharmacokinetics of Doxycycline in Channel Catfish (Ictalurus punctatus) Following Intravenous and Oral Administrations

Cheng

et al. 2020

Front. Vet. Sci.

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The objective of this study was to investigate the bioavailability (BA) and pharmacokinetics (PK) of doxycycline (DC) in channel catfish (Ictalurus punctatus) following a single intravenous injection at 5 mg/kg and a single oral administration at 50 mg/kg at 24 • C. The calculation of PK parameters was based on the software 3P97. The plasma samples were determined using ultra-performance liquid chromatography. Following oral administration, the multiple-peak phenomenon presented in concentration vs. time curve of DC at 2 h (107.01 mg/L), 8 h (55.07 mg/L), and 72 h (15.10 mg/L), respectively. The compartmental model cannot simulate the oral concentration vs. time profile beside a non-compartmental model. The calculated parameters of the elimination rate constant (λ z), the elimination half-life (t 1/2λz), and the area under the concentration vs. time curve (AUC 0-144) were 0.037 1/h, 18.91 h, and 2255.45 µg.h/mL, respectively. After intravenous administration, the concentration vs. time profile of DC was best described by a two-compartmental open model without absorption. The parameters of the distribution rate constant (α), the distribution half-life (t 1/2α), the elimination rate constant (β), the elimination half-life (t 1/2β), the apparent distribution volume at steady state (V ss), the total clearance (Cl) and the area under the concentration vs. time curve (AUC 0-∞) were 2.79 1/h, 0.25 h, 0.042 1/h, 16.51 h, 300.00 mL/kg, 14.00 mL/h/kg, and 364.99 µg.h/mL, respectively. For the calculation of BA values at the same condition, the data obtained from intravenous injection were also iterated based on a non-compartmental model, and the corresponding parameters of λ z , t 1/2λz , V z , Cl, and AUC 0-144 were 0.019 1/h, 36.26 h, 480.00 mL/kg, 9.10 mL/h/kg, and 514.45 µg.h/mL, respectively. However, there was a considerable difference in the same parameter when calculated by compartmental and non-compartmental approaches. Finally, the medium BA value of DC was evaluated to be 43.84%. This study provides future studies with a framework for determining the BA of DC in the development of a new formulation and provides information on the appropriate use of DC in aquaculture.

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Integration of pharmacokinetic–pharmacodynamic for dose optimization of doxycycline againstHaemophilus parasuisin pigs

Cited by 15 publications

References 34 publications

Pharmacokinetic/Pharmacodynamic Integration of Doxycycline Against Mycoplasma hyopneumoniae in an In Vitro Model

Pharmacokinetic/Pharmacodynamic Integration of Doxycycline Against Mycoplasma hyopneumoniae in an In Vitro Model

Effects of Single and Repeated Doses on Disposition and Kinetics of Doxycycline Hyclate in Goats

The Pharmacokinetics of Doxycycline in Channel Catfish (Ictalurus punctatus) Following Intravenous and Oral Administrations

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