Review on Population Pharmacokinetics of Amikacin in Paediatrics

Amikacin is an aminoglycoside antibiotic with a broad-spectrum bacterial coverage that is frequently utilized both as monotherapy and in combination with other antibiotics for severe bacterial infections in the paediatric population. The narrow therapeutic index of the drug and high inter-individual variabilities in drug exposure results in either drug toxicity or subtherapeutic concentrations. Thus, therapeutic drug monitoring and population pharmacokinetics are pivotal to facilitate the optimal dosage regimens in paediatrics and negate the adverse outcomes. The therapeutic goal is to maintain the target peak and trough concentrations within 30-40mg/l and <5 mg/l respectively. This review aimed to summarize population pharmacokinetic considerations and the pharmacokinetic parameters of amikacin across the paediatric population.


INtROductION
Aminoglycosides act synergistically against gram-negative organisms and certain gram-positive organisms.These are used for the treatment of severe infections of the abdomen, urinary tract, and respiratory tract infections and can also be used prophylactically. 1 Gentamicin and Amikacin are the most frequently used aminoglycosides.Toxicities have been reported due to the increased frequency of Aminoglycoside administration.Several studies have concluded that the once-daily dosing of Aminoglycosides is safe and more efficacious than the multiple dosing. 2 Amikacin, a narrow therapeutic index drug, is widely used in the paediatric population for various conditions like neonatal sepsis, hospital-acquired infections, acute respiratory tract infections, and urinary tract infections.It acts by disrupting the protein synthesis and inhibits the growth of bacteria.Due to high inter-individual variability, dosage adjustments are required. 3he most reported toxicities include irreversible ototoxicity and nephrotoxicity which is reversible when detected early.Apart from toxicities, a few adverse effects such as tingling, numbness, fever, rash have been reported. 2 h a r m a c o k i n e t i c s i s t h e st u d y of movements of drugs through the body enclosing the kinetics of absorption, distribution, metabolism, and excretion (ADME).The application of pharmacokinetic principles to the safe and effective therapeutic management of the drugs in an individual patient is clinical pharmacokinetics.Primary goals of clinical pharmacokinetics include improving efficacy and reducing the toxicity of patient's drug therapy.][6] Several studies and practice guidelines recommend a target serum Amikacin peak concentration to be 20 to 35 mg/L, trough concentrations >5-10 mg/L. 7,14,25The recommended dosing in neonates and infants is 15mg/kg IV, Once daily (OD) and 7.5mg/kg, twice daily (BD).Comparatively, the OD regimen has reduced toxicity and increased efficacy than the BD regimen. 8Amikacin has a mean half-life of 6.0 hours in neonates and 1.9 hours in children aged up to 6 years. 10arrow therapeutic drugs tend to cause toxicity.To ensure the safety of the drug a phenomenon called therapeutic drug monitoring (TDM) is performed to optimize the dosage regimen in individual patients. 9To perform TDM, 2 blood samples are collected, one peak sample to be collected 30 mins after drug administration and one trough sample should be collected 1 hour before the next dose, and quantification of the drug is performed. 10igh inter-individual variability n e c e s s i tate s t h e n e e d fo r Po p u l at i o n pharmacokinetic modeling to determine individual Pharmacokinetic parameters and source of variability in a population. 11This review presents the population pharmacokinetics of Amikacin in paediatric population among various age groups and disease conditions.

Inclusion Criteria
The following studies were included: Studies that conducted therapeutic drug monitoring, Studies that optimized dosage regimens, Studies that determined the population pharmacokinetics in the paediatric population, and Studies that suggested dosage adjustments in different disease conditions.

Exclusion Criteria
The articles which did not have the information on pharmacokinetic aspects were excluded from the study.

Population Pharmacokinetics of Amikacin
High variability in the primar y pharmacokinetic parameters influenced by multiple covariates has been established in the paediatric population.Since amikacin excretion is through renal, GFR predominantly determines the clearance values. 23Hence, in neonates there is a significant difference in the clearance of the drug when compared to adults.Gestational age is one such covariate as the preterm infants had higher drug levels than the full-term infants.The mean neonatal amikacin Vd, CL, and t1/2 were 0.78 ± 0.38 l/kg, 86.99 ± 48.22 ml/h•kg, and 6.81 ± 2.51 h, respectively. 22It was evident from a study that there was a decrease in half-life and increase in clearance with increase in the post-conceptional age.Variability has also been noted with the frequency of dosing, for instance, a study conducted by Katarina Vucicevic et al., revealed higher drug levels in the BID dosing viz peak concentration of 36.39 mg/ml and trough concentration of 5.67 mg/ml while the OD regimen produced a peak concentration of 21.79 mg/ml and trough concentration of 3.99 mg/ml respectively. 22he reported mean pharmacokinetic parameters and the influence of covariates among different pop pk studies are summarised in Table 1.

Dosage Adjustments and Pharmacokinetics of Amikacin in Various Disease Conditions
Amikacin has been used in various disease conditions and it is often co-administered with other antibiotics including Vancomycin, betalactam antibiotics.There is a higher inter-individual variability observed in ALL when compared to the normal healthy volunteers. 12The mean peak serum concentrations were observed to be 36.30±4.03µg/ml.normal healthy volunteer-19 to 43.8 mg/L.due to morphological changes in cancer patients, the renal clearance might be affected which has a direct effect on the clearance of the drug.The clearance and half-life tend to decrease in oncology patients which stated the importance of optimizing the dose of amikacin in paediatric ALL patients.In paediatric population, amikacin is widely used to treat sepsis and the patients at risk of sepsis.The burn patients' pathogenesis might result in altered vd, cl of amikacin. 13A total of 73 burn patients were included in a study to determine the pharmacokinetics of amikacin in burn patients.The multivariate analysis revealed that bodyweight-only had a significant effect on clearance and other covariates like age, sex, concomitant adm with vancomycin had no effect on cl or Vd.Also, pharmacodynamic studies should be conducted in burn patients to optimize the dosage.Drug characteristics such as weight, lipophilicity, and pH have an impact on the disease condition.In preterm and term neonates, at birth, the volume of distribution is increased but did not influence clearance.An increase in peak concentrations and lower trough concentrations suggested dosage adjustment in pre-term and term neonates. 14n Perinatal Asphyxia Treated with Hypothermia, there is a substantial decrease in the clearance of the drug by 40.6% but no change was noted in the volume of distribution.The percentage of neonates with toxic trough levels had decreased from 40 to 76% to 14 to 25% by increasing the dosing interval by 12h.Simulation of the study revealed that the neonates reaching the toxic trough levels has decreased by increasing the dosing interval by 12h which also increased the clearance.For children weighing 2.8kg, the dose recommended was 15mg/kg every 42h and 15mg/kg every 48hours for children weighing between 1.8kg to 2.8kg.15Parameters of the above-discussed disease condition have been shown in the Table 2.

Therapeutic Drug Monitoring of Amikacin to Assess Nephrotoxicity & Ototoxicity
Commonly reported toxicities of Amikacin are nephrotoxicity and ototoxicity.Several studies have been conducted to compare the safety and efficacy of once-daily and twice-daily dosing of Amikacin. 16It has been established that the trough plasma concentration of <10mg/L is safer and there exists a risk of ototoxicity when it exceeds 10mg/L and duration of therapy if it exceeds more than 7 days.The peak plasma concentration of up to 30mg/L is acceptable.Amikacin-induced ototoxicity is caused by damaging the cochlea in the inner ear which is known as cochleotoxicity leading to permanent hearing loss.It also causes calcium influx by binding to the NMDA receptors.Tinnitus is used in the early diagnosis of ototoxicity in paediatric patients. 17Extremely low-birthweight infants are at higher risk for ototoxicity compared to low birth-weight infants.Thus, dosage adjustments of Amikacin are needed based on the gestational age, birth weight. 18ephrotoxicity is yet another familiar toxicity of Amikacin predisposed by the accumulation of the drug in the proximal renal tubule, which produces oxidative damage by emitting free radicals. 19The risk of toxicity is typically more with the coadministration of other nephrotoxic drugs such as loop diuretics, NSAIDs, Amphotericin B, etc. nephrotoxicity was assessed by serum creatinine levels if >0.3mg/dl or 50% increase after the initial therapy.The simulation studies revealed significantly high variability between the plasma levels in preterm and term infants.Thus, higher risk in preterm infants than the term infants those with increased serum Amikacin levels in preterm infants have been concluded. 20

Monitoring of Ototoxicity and Nephrotoxicity
Ototoxicity is measured by an otoacoustic emission test and pure tone screening.It is screened by using audiometry, earphones.It is managed by audiological interventions such as hearing aids, educational interventions, and tinnitus therapy. 18For the prevention of nephrotoxicity, calculating creatinine clearance, baseline kidney function, and urinary alpha-1m excretion should be monitored in all the patients administered with Amikacin and therapeutic drug monitoring is essential in patients with abnormal renal function. 21

Once Daily (OD) vs Twice Daily (BD) Dosing of Amikacin
There has been a conflicting view about the safety of once-daily vs twice-daily regimens.Studies have stated that mean peak and trough concentrations 21.79 μg/ml and 5.67 μg/ml in twice-daily regimen was significantly different from peak and trough concentrations of 36.39 μg/ ml and 3.99 μg/ml of once-daily regimen but there was no change observed in the pharmacokinetic parameters. 22Some studies have concluded that the OD regimen had higher peak concentrations and less trough concentration compared to the twice-daily regimen. 16When the peak plasma concentration is higher the activity of the drug will be higher, at the same time when the trough level is below 10 mg/L ototoxicity can be prevented. 23hus, establishing the superiority of the oncedaily regimen owing to higher bactericidal effect with higher peak plasma concentration and better tolerability with lower trough plasma concentrations.cONcluSION Amikacin is a narrow therapeutic drug with high inter-individual variability.Pharmacokinetic modeling enables the individualization ratio of dosage regimens.High variability has been observed in the clearance and volume of distribution in preterm and term infants.Thus, this review article concludes that Amikacin should be administered only when it is indicated, and dosing should be rational as the Amikacin pharmacokinetic parameters.Therapeutic drug monitoring of Amikacin is necessary to optimize a safe and effective dose.Thus, further studies have to be conducted to recommend an appropriate dose for safe and effective treatment of Amikacin in paediatric population.

Figure .
Figure.Literature survey

table 1 .
Population Pharmacokinetics among Paediatric Population Title peak -Peak Concentration, T max -Time taken to reach the maximum concentration, C ave -Average Concentration, Vd -Volume of Distribution, Cl -Clearance

table 2 .
Pharmacokinetic Parameters in Various Disease Conditions Disease *AUC-Area under the curve