The Clinical Pharmacokinetics Discussion Paper
The field of pharmacokinetics has significant implication in the drug development process. Before any new drugs come in the market, its role and mechanism of action is evaluated on the basis of pharmacokinetics and pharmacodynamic parameters. Some of the important parameters in the drug development process includes clearance, concentration range, extent of availability, toxic concentration, extent of protein binding and volume distribution. Secondly, pharmacokinetics also studies the process of drug absorption, distribution and metabolism of drugs. Knowledge of these actions of drugs and the core principles of pharmacokinetics promotes effective therapeutic management of the drugs in patients (1). This drug report particularly discusses the pharmacokinetics parameters of Amikacin drugs to understand its therapeutic benefits in particular group of patients and the precautions needed while administering the drug to patients The Clinical Pharmacokinetics Discussion Paper.
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Amikacin is an aminoglycoside antibiotic used in the treatment of serious bacterial infections particularly gram-negative bacterial strains like Escherichia coli, Pseudomonas species, Acinetobacter species and Enterobacter and other species. It is mainly involved in inhibiting the production of bacterial proteins consequently leading to bacterial cell death. Amikacin is a semi-synthetic antibiotic derived from Kanimycin A and it binds to the 30S ribosome of infectious organism to disrupt and inhibit bacterial protein synthesis. The binding of the aminoglycoside antibiotic to bacterial 30S ribosomal unit causes misreading of the t-RNA. The inhibition of translocation prohibits the ability of the bacteria to synthesize vital proteins necessary for its growth. This action of the drugs lead to the production of the non-functional or toxic peptides that contributes to the bactericidal effect of the drug (2). The resulting bactericidal activity is fatal for aerobic gram-negative bacilli The Clinical Pharmacokinetics Discussion Paper.
Use of Amikacin drug is often associated with serious side effects such as shortness of breath, rashes, swollen lips and tongue causes due to allergic reaction, dizziness, diarrhoea, skin tingling and muscle twitching. Use of aminoglycoside drugs like Amikacin has the potential to cause auditory, renal, vestibular toxicity and neuromuscular blockade (3). Another study also suggested Amikacin-induced liver toxicity seen due to ultrastructural changes in liver. Hence, patients with chronic liver disease has the risk of nephrotoxicity. Dosage consideration may help to lessen risk in vulnerable people (4). The following are the toxicity of the drug in different areas-
Renal- The nephrotoxicity of the drug is associated with renal function changes such as increase in serum creatinine, albuminuria and red and white blood cells. Nephrotoxicity is high in patients with impaired renal function who receive prolonged treatment. Other manifestations of neurotoxicity includes numbness, skin tingling, convulsion and muscle twitching (5)The Clinical Pharmacokinetics Discussion Paper.
Nervous- Rare adverse effects include tremor and headache. Other adverse outcome of the drug include neuromuscular blockade, toxic effect on eights cranial nerves, loss of balance, hearing problem and vertigo. This indicates possibility ototoxicity due to cochlear hair cell damage which is often irreversible. Often the drug is used with diuretics, however it should be avoided because diuretics may also cause ototoxicity (3).
Respiratory- In very rare case, respiratory paralysis or apnea is observed due to neuromuscular blockade after parenteral injection of the drug. These adverse symptoms should be checked in patients who have to take neuroblocking agents like tubocurarine (3).
Amikacin is mainly given in the form of injection for the short term treatment of serious infection caused due to different strains of gram negative bacteria. Clinical studies reveal the efficacy of the drug in treating bacterial septicaemia and infection in the respiratory tracts, bones and central nervous system (6). Its clinical indication is also seen in treating post operative infections and peritonise caused due to intra-abdominal infection (7). In some case, Amikacin sulphate injection is also given to patients with urinary tract infection when causative organism is not affected by antibiotics having less toxicity (8)The Clinical Pharmacokinetics Discussion Paper.
While proceeding with the treatment, it is necessary that susceptibility testing is done to identify the susceptibility of the drug to different causative organisms. In the initial phase, the therapy may continue and the decision to continue the drug should depend upon the susceptibility test, response of the drug in patient, severity of the infection and adverse effect of the drug (9).
The calculation of correct dosage is dependent on body weight of patients before treatment. Secondly, renal function assessment should be done to measure creatinine concentration. Amikacin concentration in serum is also necessary to check that they are not at excessive level. During the therapy, the peak concentration after injection above 35mcg/ml and trough concentration (concentration before next dosage) above 10mcg/ml should be avoided (10). The following is the dosage information for Amikacin drugs in different patients- The Clinical Pharmacokinetics Discussion Paper
For treating bacteremia, initial dose should be 1.5g/day and the dose should be adjusted later based on desired serum level.
In case of nosocomial pneumonia, 20mg/kg/day IV is necessary by dividing it into 3 dose for one day. The duration of the treatment should be kept to 7 days to reduce the risk of infection from resistant organism (11).
The physicochemical nature of drugs determines their pharmacokinetic properties such as metabolism, absorption, distribution and drug clearance. Amikacin is a broad spectrum antibiotic with aliphatic heteromonocyclic structure. The chemical nature of the drugs is highly soluble in water, low plasma protein binding and great clearance (12). The molecular feature of Amikacin determine the interaction with enzyme and predict feature that might lead to enzymatic degradation of the drugs. Secondly, the route of clearance is also dependent on molecular properties of Amikacin such as charge, atomicity, molecular size and its hydrogen bond acceptors. The molecular weight of Amikacin is 683.68g/mol. The renal excretion is inversely related to level of plasma protein binding too (23)The Clinical Pharmacokinetics Discussion Paper.
Amikacin is highly water soluble drug, has low plasma protein binding and more than 95% excreted by the kidney (12). Amikacin belongs to the class of aminoglycoside drugs derived from Kanamycin A. Its molecular formula is C22H43N5O13 •2H2SO4 (13). The following is the detail regarding pharmacokinetics parameters of Amikacin drugs-
ADME
Absorption-The drug is generally taken as intravenous or intramuscular route because amikacin is not absorbed orally. In case of adults with normal renal function who are given a single dose of 7.5mg/kg, the peak plasma amikavin concentration is achieved within 45 minutes to 2 hours. It indicates that the drug is rapidly absorbed after the intramuscular administration. Its injection mainly consist of sulphate salts as shown below-
Figure1: Structure of Amikacin (13)
Distribution- Following the administration of the required dosage of the drug, the drug is distributed into bile, bronchial secretions, pleural and synovial fluids and interstitial fluid. This indicates that Amikacin remains in the extracellular fluid space of patients.
Metabolism- After the distribution of the drug, peak serum level demonstrates the efficacy of the drug and the trough serum level determines the toxicity of Amikacin. In patients taking multiple dose per day, peak serum level is 15-30mcg/ml and trough serum level is 1-4 mcg/ml. Aminoglycosides are efficient if the peak concentration is more than the minimum inhibitory concentration of the microorganism.
Elimination- In adults with normal renal function, the plasma elimination half life of amikacin is 2-3 hours and this increases by 30-86 hours in patients with chronic renal impairment. The clearance of the drug is severely low in patients with renal impairment with decrease in clearance along with the increase in severity of impairment (13)The Clinical Pharmacokinetics Discussion Paper.
Volume of distribution (Vd)-The volume of distribution of Amikacin drug is 0.21 ± 0.08 L/kg (14). The volume of distribution is related to the extracellular fluid content of the body and maintaining fluid balance will be important when estimating the volume of distribution of the drug in patients. Amikacin is given as 250mg/ml injection and in new born of different weights, the recommended dose is 7.5mg/kg. This volume of distribution of the drug indicates that aminoglycosides like amikacin remains in the extracellular fluid space of neonates. In normal adults, it is rapidly absorbed after intramuscular administration and peak serum concentration after 1 hour is 12 mcg/mL for 250mg single dose (15)The Clinical Pharmacokinetics Discussion Paper.
Total clearance (CL)- The total clearance rate of Amikacin drug is 78.6 ± 12.1 mL/min/kg and this based on the creatinine clearance. The mean serum clearance rate is about 100mL/min and renal clearance rate is 94 mL/min in patients in normal renal function (14). The creatinine clearance calculation is dependent on age, weight, sex and amount of serum creatinine in the body of patients. The serum creatine values have relation with aminoglycoside half-lives in patients and dose schedule should be adjusted according to clinical observation of patients.
Half-life (t1/2)- The estimated half life value of Amikacin is 1.4 ± 0.41 hours. It indicates that elimination occurs within 2-3 hours. Serum half lives correlates inversely with post-natal age and renal clearance of amikacin. In normal adults, half life is slightly above 2 hours and average volume of distribution of about 24 liters. In case of patients with renal impairment, the serum half life is prolonged due to the slower excretion of the drug. Therefore, before giving the drug to patients with renal impairment, renal function should be observed carefully and dose should be adjusted accordingly (14). Combination of sulbactam and amikacin therapy helps to reduce hematological disease and complications. Secondly, serum concentration of the drug also determines its use for different clinical purposes (16).
Therapeutic drug monitoring is the analysis of the drug concentration in the blood. This analysis is important to improve the outcome in special group of patients by the adjustment of the dose of the drugs. The drug concentration data can be interpreted by means of time, route, dose given to patients, validity of the pharmacokinetic parameters and the handling and storage consideration of the drug (17)The Clinical Pharmacokinetics Discussion Paper.
The anti-bactericidal activity of the drug is seen after peak concentration is reached after drug injection. Clinical recovery of patient is achieved when the peak concentration of the drug is greater than the minimal inhibitory concentration of the pathogen. However, conditions like sepsis alter the pharmacokinetic property of the drug. Secondly, conditions like renal impairment also results in accumulation of the drug. In such case, use of higher than recommended dose cause elevated trough concentration and consequently increase in toxicity (18). Hence, in different clinical context and condition of patients, the daily dose of drugs needs to be adjusted to achieve optimal drug concentration.
One research study has showed that the pharmacokinetic property of Amikacin drug is changes in patient with sepsis and in such case dose adjustment is necessary (18). This is also required in patients with renal or hepatic impairment. This is because of high nephrotoxicity of the drug. While giving the drug to renally impaired patient, it is necessary to adjust dose based on creatinine clearance calculation. However, this is difficult in acute renal impairment where patients renal function changes rapidly. While initiating therapy in such patient, it is necessary to treat the infection aggressively for first 24 hour and then reduce the dose after monitoring the renal function of patients from time to time (19). This is the reason why dosage formulation of the drug changes in patient with urinary tract infection, hospital acquired pneumonia and renal impairment (22). The dose modifications for renal impairment according to age and creatinine clearance (CrCl) are as follows-
CrCl greater than 90 mL/min and age more than 60 years- q8 hrs
CrCl between 60-90 mL/min and age less than 60 years- q12hrs
CrCl of 25-60mL/min- q 24hrs
CrCl of 10-25 mL/mim- q 48 hrs (20)
Just like patients with renal impairment, dose adjustment is also necessary in patients with hepatic impairment. As there is no marker for hepatic clearance, drug dosing consideration becomes difficult. Hence, to predict the kinetic behavior of drugs in cirrhotic patients, drugs should be used according to level of hepatic extraction. The higher the hepatic extraction of the drug, the higher the bioavailability in patients. On this basis, the dose is adjusted irrespective of the route of administration (21)The Clinical Pharmacokinetics Discussion Paper.
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Conclusion
The drug report on Amikacin summarized the therapeutic efficacy of the drugs in the treatment of severe bacterial infection. The pharmacological study of the drug revealed it function in binding to the bacterial proteins and thus inhibiting its growth. This property lends the drug its bactericidal effect. However, the clinical usage and dose formulation suggest the action of the drug changes in specific population group. In such instance, therapeutic drug monitoring is an essential technique to understand the pharmacokinetic properties of the drug and this will help to alter and change the dose formulation of drug in patients with renal and hepatic impairment. The Clinical Pharmacokinetics Discussion Paper