Phamacokinetics of Levofloxacin in Chronic Kidney Disease

INTRODUCTION

According to principles of Clinical Pharmacokinetics, the magnitude of drug action, whether therapeutic or otherwise, has a positive relationship with the concentration of a drug in the blood stream and this is true for most, but not for all drugs employed clinically for therapeutic purposes. Hence, if plasma concentration of the drug is too low, there would be therapeutic failure, (i.e. ineffective; if too high there could be toxicity) especially for drugs which are potentially toxic. An optimal response would be achieved when the plasma drug concentration is within the therapeutic range, termed “Target Concentration”.

The concentration of a drug in the blood stream at any moment is determined by the dose size, i.e. the amount of drug administered, the extent of its absorption from the site of administration (bioavailability), its distribution to different sites of the body, and its elimination by either biotransformation (destruction) or excretion (removal) or both.

Antibacterial agents, most of which are antibiotics, are used for eradication of pathogenic bacteria that have invaded the host to cause infections. To do so they have to reach a critical concentration at the site of infection or indirectly in the blood stream in case of systemic administration, called “Minimum Inhibitory Concentration (MIC)”. Antibacterial agents are broadly categorized into : (a) bactericidal agents that directly kill off all the invading bacteria. To do so the drug needs to reach the MIC with each dosing, but the concentration need not be maintained continuously throughout the course of treatment and (b) bacteristatic agents that prevent the proliferation and growth of bacteria, letting them to be destroyed by the host’s immune system. To be effective, the drug concentration at the site of infection, hence in the blood stream must be maintained throughout the course of therapy.

Some antibacterial agents act on the specific sites or cell components of the bacteria which are not present in mammalian cells, e.g. cell wall and are considered non-toxic to humans even at relatively high doses. In contrast, some antibacterial agents act at sites in bacteria that are also present in mammalian cells; e.g. DNA, RNA, nucleotides, specific enzymes etc., and are potentially toxic to the host especially with doses above the therapeutic range. Obviously for the latter group, dosage adjustment is required to prevent adverse effects. This can be done by monitoring the plasma drug levels in acccordance with the principles and parameters of Clinical Pharmacokinetics.

In the present study the pharmacokinectic parameters of levofloxacin were assessed and compared in normal patients as controls, and patients with chronic kidney disease (CKD).

Levofloxacin is a newer antibacterial agent of the fluoroquinolone group. It is the laevo (L) isomer, the active components of the parent compound ofloxacin. Like all other fluoroquinolones, levofloxacin produces its antibacterial action by inhibiting DNA replication and transcription through inhibition of DNA gyrase enzyme ^(1,2). It is a bactericidal agent that causes concentration- dependent killing of bacteria ^(3,4). It is active against a wide range of Gram negative and Gram positive microorganisms. According to Fu et.al.(1992), levofloxacin is several times more potent than other fluoroquinolones, e.g. ofloxacin, ciprofloxacin, and against all 801 microorganisms tested, including: Staph. aureus, Enterobacteriaceae, Proteus, Pseudomonas, Mycobacteria etc5. It is indicated for treatment of bacterial infections of the respiratory system, urinary tract, skin, prostate, and inhalation anthrax.

Levofloxacin is rapidly (T_max 0.8 _ 2.4 hr) and almost completely (Bioavailability 99%) absorbed from the GI tract, such that the oral route and intravenous route (by 1 hour infusion) of levofloxacin can be considered interchangeable⁶. It is widely distributed in the body and has extensive intracellular penetration. In fact, levofloxacin concentrations in many tissues and body fluids are similar to or substantially higher than those observed in plasma⁷. Levofloxacin undergoes limited metabolism (biotransformation) in humans and is mainly excreted unchanged in the urine. Following a single oral dose of 500 mg, 79.60% of it was recovered in urine as unchanged drug in 24 hours6. Hence renal function, assessed as creatinine clearance (CL_CR) plays the most important role in elimination of levofloxacin. According to Ortho-McNeil Pharmaceutical (2011), plasma elimination half-life (T_1/2) in healthy subjects ranges from 6-8 hours (6.4 ± 0.7 hr). T_1/2 of levofloxacin in patients with CL_CR 50-80 ml/min is 9.1±0.9 hr, in patients with CL_CR 20- 49 ml/min is 27±10 hr, and in those with CL_CR <20 ml/min is 35±5 hr8. Administration of the drug with the same or usual dosage interval (i.e. in between doses), longer half-life would lead to more cumulation of the drug in the body and higher plasma drug concentration, even up to toxic levels.

In general, fluoroquinolones including levofloxacin are well tolerated. At therapeutic doses minor adverse reactions involve the GI tract: nausea, vomiting and/or abdominal discomfort. CNS side-effects include: mild headache, lightheadedness, drowsiness, insomnia² and more serious adverse reactions include tendonities and Achilles tendon rupture. In case of levofloxacin, symptoms can also include irreversible peripheral neuropathy, QT prolongation/Torsades de pointes, toxic epidermal necrolysis, Stevens Johnson Syndrome, fatal hypoglycemia, granulomatous nephritis, serious visual complications, etc. Incidence of adverse reactions is low as some of them are dose- related; tendonitis and Achilles tendon rupture occur more commonly in patients over 60 years of age. Presumably, some may also be related to dosage and plasma drug concentration achieved. For drugs which are extensively excreted unchanged from the kidneys, e.g. levofloxacin, renal function is the main determinant of plasma concentration achieved with a specific dose.

MATERIALS AND METHODS

The study was done on patients of both genders from the New Yangon General Hospital and Workers’ Hospital, Yangon. Drug assays were done at the Common Research Laboratory, University of Medicine (1) Yangon.

Patients who were admitted to the above hospitals and those who needed levofloxaxin treatment were selected. Subjects of the study consisted of :

(a) 10 patients with normal renal function
(b) 10 patients with stage 2 chronic kidney disease (CKD), CL_CR 60-89 ml/min
(c) 10 patients with stage 3 CKD, CL_CR 30-59 ml/min

After getting written informed consent, having done base-line investigations and ensuring the absence of allergy for fluoroquinolones, each subject was administered 500 mg of levofloxacin by intravenous infusion over 60 minutes :
(1) Firstdose:atthestartofexperimentonDay 1
(2) Second dose: 24 hours after the first dose on Day 2
(3) Third dose: 24 hours after the second dose on Day 3.
(4) 3 ml of venous blood at a time was collected from each subject:
– At 0,1,2,4,6 and 12hours of drug administration on Day 1 for plasma drug concentration-time graph.
– Just before and again 1 hour after drug administration of second and third doses, to determine the minimal (trough) and maximal (peak) plasma drug concentrations achieved with the dosing regimen instituted.

Blood samples were collected in heparinized tubes, mixed gently and centrifuged at 3000 rpm for 10 minutes. The separated plasma were collected and stored at -20°C prior to analysis.

Base-line cardiovascular status (heart rate, blood pressure, ECG) was recorded before drug administration and after the third dose, to determine the cardiovascular side-effects of the drug.

Concentration (content) of levofloxacin in each of the samples collected was assayed by High performance Liquid Chromatography (HPLC) method of Gao et al (2007) ⁽⁹⁾. For each particular category of sample e.g. second hour sample of Controls, at Day 1; pre-dosing sample of stage 2 CKD subject at Day 2; post-dosing sample of stage 3 CKD subject at Day 3, etc., the mean was calculated. With the results thus obtained, the following statistical analyses were carried out for different categories of subjects, i.e., Controls, Stage 2 and Stage 3 CKD subjects, separately :

RESULTS

Since the drug was administered intravenously, the plasma drug concentration-time graph showed both α and β phases of elimination (Figure 1). The former is due to redistribution of the drug from plasma to extravascular compartment, and the latter due to elimination of the drug from plasma. Pharmacokinetic parameters were measured/calculated form the β phase.

DISCUSSION

Levofloxacin was administered intravenously in the study to ensure complete bioavailability (f=l), i.e. all the administered drug reached the blood stream. This simplified the calculation of pharmacokinetic parameters.

Plasma drug concentration-time graph is the essential first step for calculation of pharmacokinetic parameters of the administered drug. From this graph the pharmacokinetic parameters are derived by measurement (AUC, C_max, T _1/2) or by calculation employing appropriate formulae (V_d, K_el, CL).

C_max

The maximum plasma drug concentration achieved with intravenous 500 mg of levofloxacin was not significantly different between control and test subjects, but C_max was higher in subjects with third degree CRD.

Plasma drug concentration achieved at any moment is determined by the rate at which the administered drug is absorbed, its distribution at the vascular and extravascular compartments, and the rate at which it is eliminated from the plasma. In the present study , the rate of absorption was constant in all subjects since the drug was uniformly administered by intravenous infusion. Being the same drug, distribution between vascular and extravascular compartments would be similar. In the time that C_max is achieved (i.e. within 1 hour) elimination of the drug from plasma, in this case by renal excretion, would not be much different. Hence C_max achieved by different categories of subjects (controls, second and third degree CRD), even if different, would not be statistically significant.

T_1/2

Plasma half-life or elimination half-life is the indicator of the body’s capacity to eliminate the drug from plasma. It is obtained by the measurement from the β elimination curve of plasma drug concentration-time graph. Decreased elimination leads to a higher plasma drug concentration at any specified time frame, resulting in a gentler slope (less steep) of the elimination curve and longer half-life (Figure 1). Longer half-life thus indicates a decreased ability of the body to eliminate the administered drug.

In the present study, the half-lives were increased (prolonged) to a statistically significant degree in subjects with both second degree and third degree CRD, as compared to that of the Controls. According to literature,^(6,8) levofloxacin is mainly eliminated by being extensively excreted unchanged from the kidneys. The difference in renal function, as evidenced by the difference in creatinine clearance, therefore, probably explains the difference in T_1/2 of levofloxacin between Controls and CRD subjects.

Peak and trough plasma drug levels on Day 2 and Day 3

The highest plasma drug concentration achieved (peak) by administration of 600 mg of levofloxacin intravenously was practically identical on Days 1, 2 and 3 in control subjects. In contrast, both the peak plasma drug concentration after administration of the drug, and trough (the lowest plasma drug concentration just before administration of the next dose) were increased significantly with administration of the second and third doses in second and third degree CRD subjects on Days 2 and 3 of the study.

In subjects with normal renal function (Controls), T_1/2 of levofloxacin is 6.4 ± 0.7 hrs. This precluded accumulation when the dose of the drug is repeated in 24 hours, and C_max is similar with every subsequent dose, according to “single dose kinetics”⁽¹⁰⁾. According to literature⁽⁸⁾ half – life of levofloxacin in patients with creatinine clearance 20-49 ml/min is increased to 27 ± 10 hrs. This implies that for drugs which are extensively excreted by the kidneys, decreased kidney function (evidenced by creatinine clearance) would lead to longer plasma half-life. In the present study, plasma half-life of the drug was significantly increased in subjects with CRD (see above). Longer half-life could result in accumulation of the drug, leading to higher peak and trough with subsequent doses, as in the case of “multiple dose kinetics”.

Adverse Reactions

For those drugs which produce dose- related adverse reactions, an increase in plasma drug concentration over the therapeutic or “Target” concentration, for any reason, would lead to more untoward effects.

In the present study, no cardiovascular adverse effects were detected in any of the subjects throughout the study, even though plasma drug concentration of levofloxacin was significantly increased in both CRD subjects. It may be assumed that the possible adverse reactions of levofloxacin listed above are not directly related to innate pharmacological properties of the drug; at any rate, they seem not to be dose-related.

CONCLUSION

The present study has shown that for drugs that are eliminated from the body by being extensively excreted via the kidneys, e.g. levofloxacin, impaired renal function can increase the plasma drug concentration achieved, over the intended or “Target” concentration, especially with repeated doses. It implies that for drugs that produce dose-related toxicity, i.e. have narrow therapeutic index, dosage adjustment need to be made in the presence of renal impairment, so that adverse effects of the drug are prevented.

REFERENCES