Influence of activated charcoal on the pharmacokinetics of moxifloxacin following intravenous and oral administration of a 400 mg single dose to healthy males

Abstract

Aims

To evaluate the extent to which enterohepatic recycling circulation contributes to moxifloxacin bioavailability in healthy, males by administration of activated charcoal and to evaluate the efficacy of activated charcoal administration in decreasing systemic concentrations of moxifloxacin in the event of overdose.

Methods

Nine healthy males, mean age 34 years (range 23–45 years) participated in a single centre, randomized, nonplacebo-controlled, three way crossover study. The pharmacokinetics of moxifloxacin in plasma and urine were determined for up to 96 h following a 400 mg single dose randomly administered on three separate occasions with a minimum washout phase of 1 week. Treatment A was 400 mg moxifloxacin IV as a 1 h infusion, treatment B was 400 mg moxifloxacin IV as a 1 h infusion with oral activated charcoal (5 g directly before the start of the infusion, 5 g immediately after the end of the infusion, and 10 g at 2, 4 and 8 h after the start of the infusion), treatment C was 400 mg oral moxifloxacin with activated charcoal (10 g 15 min before and at 2, 4 and 8 h after drug administration). The subjects underwent a series of clinical and laboratory tests.

Results

Single 400 mg doses of moxifloxacin (PO and/or IV) were safe and well tolerated. The bioavailability of moxifloxacin was significantly decreased when given with charcoal (AUC = 35.5 (IV reference) vs 5.40 (PO) vs 28.5 (IV) mg l⁻¹ h). Concurrently peak concentrations were lowered C_max = 3.38 (IV reference) vs 0.62(PO) vs 2.97 (IV) mg l⁻¹) by approximately 85% (P < 0.05) following oral administration and by 20% after IV treatment (P < 0.05). Bioavailability amounted to 15.4% (95% confidence interval 9.6, 25.0%) for treatment B while it was 80.4% (95% confidence interval 76.3.6, 84.6%) for treatment C. Terminal half-lives were not affected. The kinetics of urinary excretion corroborated these findings.

Conclusions

The results of this study show that moxifloxacin undergoes pronounced enteric recycling after systemic uptake. In addition, these findings confirm that activated charcoal may be useful in treating moxifloxacin overdose by preventing its absorption.

Introduction

Activated charcoal is important in clinical practice as a tool for the management of drug or chemical overdose. Enterally administered compounds are effectively bound due to its large surface and high adsorption capacity thereby preventing systemic uptake from the gastrointestinal tract. A number of pharmacokinetic studies in healthy subjects have been conducted to evaluate the efficacy of antidotes in the management of drug overdose [1–9].

Activated charcoal has also been used to understand better the pharmacokinetics of fluoroquinolones. Based on animal and in vitro data these drugs have been found to undergo transepithelial transport processes leading to either transintestinal elimination or recirculation [10–13, 15, 16] It has been shown that transepithelial transport of these drugs occurs in humans in vivo [17–23]. Charcoal has been used extensively to elucidate the enteral transport of ciprofloxacin which is predominantly excreted via active renal elimination. Ideally, a comparison of the mass balance in healthy subjects with that of patients with impaired renal elimination suggested that the drug underwent transintestinal elimination [17]. Subsequently, oral administration of activated charcoal was given to block the (re) absorption of ciprofloxacin administered as a single intravenous infusion to healthy subjects. Eighteen percent of the drug was shown to undergo intestinal elimination [18, 19]. Charcoal has also been used as a probe to predict the pharmacokinetic behaviour of fluoroquinolone metabolites [24, 25].

Moxifloxacin is currently used worldwide in the treatment of respiratory tract infections and has received recent approval for the sequential intravenous and oral treatment of hospitalized patients. It is a fourth generation fluoroquinolone, and has improved activity against Gram-positive cocci, aerobic, anaerobic, intracellular bacteria, and ‘atypical’ organisms such as Mycoplasma and Chlamydia compared with third generation agents. Its pharmacokinetic properties are characterized by complete absorption, high bioavailability (approximately 91%) and rapid penetration into target tissues. Moxifloxacin is cleared both renally and by the liver both as unchanged drug and conjugated metabolites [26, 28, 30] This allows once daily oral dosing without the need to adjust the dose in renal impairment or liver insufficiency [26, 29].

This study aimed to determine the efficacy of activated charcoal to prevent absorption of moxifloxacin in the event of overdose. In addition, we investigated the hypothesis that the drug undergoes recirculation. Earlier studies suggested this and also that the absorption characteristics of moxifloxacin along the gastrointestinal tract may differ from other quinolones [13, 14, 16].

Methods

Subjects

After having received detailed information about the study, nine healthy males (mean age 34, range 23–45 years, body mass index mean ± s.d. 26.5 ± 2.9, range 21.7–30.8) were enrolled. A sample size of at least six subjects was considered sufficient for accurate statistical assessment of the study objectives with adequate accuracy in this exploratory trial, assuming a within-subject coefficient variation of the log-transformed AUC of approximately 10%, which corresponds to previous clinical pharmacokinetic experience [28, 30]. Each subject provided written informed consent, and the study protocol was approved by an independent ethics committee (North Rhine Medical Council, Düsseldorf, Germany). The study was conducted in accordance with the Declaration of Helsinki (1964) in the revised version of 1996 (Somerset West), the ICH GCP Guideline (Note for Guidance on Good Clinical Practice) and the German drug law (AMG).

Design

The study had a single-centre, single-dose, randomized, nonblinded, nonplacebo-controlled, crossover design. Subjects received the following dosing regimens on separate occasions after an overnight fast:

1. 400 mg moxifloxacin IV as a 1 h infusion,

2. 400 mg moxifloxacin IV as a 1 h infusion with oral administration of activated charcoal (5 g immediately before starting the infusion, 5 g at the end of infusion, and 10 g at 2, 4 and 8 h after the start of infusion),

3. 400 mg moxifloxacin orally with oral administration of activated charcoal (10 g each 15 min before and at 2, 4 and 8 h after drug administration).

The three treatments were separated by a minimum washout period of at least 1 week. The timing of charcoal administration was optimized to extend the interaction with moxifloxacin over a period accounting for (a) more than 90% of systemic drug exposure based on the absorption characteristics of the drug [14, 16], (b) an expected transit time of charcoal in the gut of approximately 24 h [32], and (c) data showing that 1 g of charcoal is able to completely adsorb 400 mg of moxifloxacin.

Blood and urine sampling

Venous blood samples were taken before the administration of moxifloxacin (0 h) and then at 0.5, 0.75, 1, 1.25, 1.5, 2, 2.25, 2.5, 3, 4, 4.25, 4.5, 5, 6, 8, 8.25, 8.5, 12, 24, 48, 72 and 96 h after dosing to determine plasma moxifloxacin concentrations. Venous blood (3 ml) was collected into NH₄-heparinate coated tubes, and the samples were centrifuged within 15 min of collection for 5 min at 1600 g at 5 °C. The plasma samples were then transferred to polypropylene tubes, frozen and stored at −20 °C until analysis.

Urine was collected before drug administration (blank) and then at 0–4, 4–8, 8–12, 12–24, 24–48, 48–72 and 72–96 h after dosing. The volume of each urine fraction was recorded and a 5 ml aliquot was frozen and stored at −20 °C until analysis.

Analysis of moxifloxacin

Plasma and urine concentrations of moxifloxacin were determined by a validated HPLC method with fluorescence detection [27]. The limit of quantification was 10 µg l⁻¹. Quality control samples produced from blank plasma spiked with known concentrations of the drug (3 mg l⁻¹, 0.5 mg l⁻¹, 30 µg l⁻¹) were stored and analyzed together with the study samples. In plasma and urine interday precision (specification ≤ 20% throughout the working range) ranged from 1.3 to 5.4%, and 3.0–5.1%, respectively. Accuracy (specification 90–110% throughout the working range) was always within the range 100.9–105.7% in plasma and 102.4–108.5% in urine.

Pharmacokinetic analysis

Pharmacokinetic parameters were calculated using noncompartmental methods [31]. Peak concentrations (C_max) and time to reach C_max (t_max) were determined directly from individual plasma concentration vs time curves. AUC (area under the curve after single dose administration extrapolated to infinity) determination was based on the linear trapezoidal rule in the ascending part of the plasma concentration vs time curve, and the log-linear trapezoidal rule in the descending part. λ_z (the apparent terminal log-linear disposition rate constant) was derived from the terminal slope of the logarithmic plasma concentration vs time profile. t_1/2 (apparent terminal half-life) was obtained by linear regression analysis after log-transformation of the data using not less than three data points. AUC_norm and C_max,norm were calculated by normalizing the data to the dose and the body weight. The mean residence time (MRT) was determined as AUMC/AUC, where AUMC is the area under the first moment of the concentration-time curve determined by integrating the product of time and concentration from 0 to infinity. The volume of distribution at steady state was calculated according to V_ss = CL × MRT (CL = Dose/AUC after intravenous administration). The amount of excreted unchanged drug into urine (Ae_ur) and the renal clearance (CL_R calculated from the expression , where t_n is the time of the last data point) were also determined.

Statistical analysis

AUC and C_max were analyzed assuming log-normally distributed data. To compare pharmacokinetics between treatments, the logarithms of these parameters were analyzed using analysis of variance (anova) including sequence, subject (sequence), period and treatment effects. Based on these analyses, point estimates (LS-Means) and exploratory two-sided 90% confidence intervals for the ratios ‘IV treatment with charcoal’ and ‘PO treatment with charcoal’, respectively, vs‘IV reference treatment’ were calculated by re-transformation of the logarithmic data using the intra-individual standard deviation of the anova.

Results

Of the nine subjects enrolled in this study, seven completed all of the treatment regimens and two subjects dropped out prior to moxifloxacin administration. The treatments were well tolerated, and only eight adverse events were reported by four subjects. Treatment related adverse events were reported by two subjects during each of the three treatments. All the adverse events were of mild severity, their relationship to the study medication was judged as ‘none’ (hypertonia, pharyngitis, maculopapular rash) or ‘unlikely’ (two cases of headache, ear pain/tinnitus). Treatment was given for headache (1 × 1000 mg paracetamol), rash (triamcinolone acetonide several times daily), and ear pain/tinnitus (Panotile® 3 × 2 drops a day). All adverse events resolved completely. A few mild and transient elevations of laboratory parameters were observed, but no clear pattern of onset or duration was apparent. The changes were either pre-existing or occurred during the follow up and therefore were not considered to be clinically relevant. ECG investigations showed a QTc prolonging effect of the order of magnitude observed in previous studies. There was no clinically relevant influence of the study drug on vital signs.

The plasma moxifloxacin concentration vs time curves for each treatment group are shown in Figure 1 and pharmacokinetic parameters are summarized in Table 1. Plasma concentrations following intravenous treatment were generally detectable for at least 72 h, and those after oral administration with charcoal up to 48 h in the majority of the cases. Co-administration of activated charcoal markedly decreased plasma concentrations (IV > IV + charcoal >> PO + charcoal). In all three treatments, a biphasic decline in plasma moxifloxacin concentrations was detectable in the terminal phase. This was less pronounced during oral treatment due to the absence of plasma concentration data beyond 48 h. No obvious differences in shape of these plots were detectable at the times of charcoal administration (10 g during dose administration and at 2, 4 and 8 h).

Figure 1.

Plasma-concentration vs time profiles for moxifloxacin following a single 400 mg dose given intravenously or orally with and without co-administration of charcoal (geometric mean, SD). A: 400 mg IV as 1 h infusion, B: 400 mg IV as a 1 h infusion with charcoal, C: 400 mg PO with charcoal. 400 mg i.v. (▴); 400 mg i.v. + charcoal (□); 400 mg p.o. + charcoal (•)

Table 1.

Pharmacokinetic parameters for moxifloxacin in plasma and urine following a single oral dose of 400 mg drug with oral activated charcoal (combi PO), and given intravenously with (combi IV) and without (mono IV) oral activated charcoal, respectively (n = 7, geometric mean/SD, range)

Parameter	Mono IV	Combi IV	Combi PO
AUC (mg l−1 h)	35.5/1.15 (31.1–46.8)	28.5/1.13 (25.3–35.8)	5.40/1.92 (2.98–18.2)
AUC(0,12 h) (mg l−1 h)	19.4/1.10 (17.5–23.1)	16.9/1.08 (15.92–19.2)	3.18/1.96 (1.51–10.7)
Cmax (mg l−1)	3.38/1.22 (2.71–4.13)	2.97/1.13 (2.37–3.44)	0.618/2.07 (0.211–1.84)
tmax† (h)	1.00 (0.75–1.50)	1.00 (0.50–1.50)	0.75 (0.50–1.25)
t1/2,24 h (h)	10.7/1.10 (9.0–11.7)	8.8/1.11 (7.6–10.1)	9.6/1.09 (8.9–11.5)
t1/2, 48 h (h)	11.6/1.11 (10.0–14.0)	11.8/1.06 (10.9–12.8)	10.8/1.12 (9.5–13.2)
t1/2, 72 h (h)	12.6/1.10 (11.7–15.5)	13.0/1.07 (11.6–13.9)	11.2/1.16 (9.6–13.8)
t1/2 (h)	14.3/1.18 (11.7–17.5)	14.3/1.13 (12.6–17.0)	11.2/1.16 (9.58–13.8)
Vss (l kg−1)	2.01/1.14 (1.55–2.32)	2.28/1.15 (1.78–2.74)
CL, CL/F (l h−1)	11.3/1.15 (8.54–12.9)	14.0/1.13 (11.2–15.8)	74.1/1.92 (21.9–134)
CLR (l h−1)	3.07/1.19 (2.43–3.84)	3.34/1.23 (2.43–4.34)	3.48/1.16 (2.78–4.15)
Aeur* (%)	27.5 ± 5.5 (18.8–34.6)	23.9 ± 3.7 (19.1–28.2)	6.1 ± 5.7 (2.27–18.5)

^*arithmetic mean ± SD.

^†Median (range)

The absolute bioavailability of intravenously administered moxifloxacin was significantly decreased by approximately 20% (P < 0.05) when charcoal was given concomitantly with the drug, whereas it decreased by approximately 85% (P < 0.05) after concomitant oral administration (Table 2).

Table 2.

The influence of activated charcoal on the absolute bioavailability of intravenous and oral moxifloxacin in healthy males (LS-means of ratios (see legend) with two-sided 90% confidence intervals on the primary pharmacokinetic parameters AUC and C_max, n = 7)

Analyte	Ratio	Parameter	n	Estimated ratio (LS-mean, %)	95% confidence interval
Moxifloxacin	Combi PO/Mono IV	AUC	7	15.4	9.6, 25.0*
		Cmax	7	18.5	11.9, 28.7*
	Combi IV/Mono IV1	AUC	7	80.4	76.3, 84.6*
		Cmax	7	86.6	73.0, 102.8

Combi PO = 400 mg oral moxifloxacin together with 40 g of activated charcoal given in 4 portions 15 min before, 2, 4 and 8 h after administration, Combi IV = 400 mg intravenous moxifloxacin (1 h infusion) together with 40 g activated charcoal given in 4 portions immediately before, 2, 4 and 8 h start of infusion, Mono IV = reference treatment with 400 mg IV moxifloxacin infused at a constant rate over 1 h.

^*P < 0.05.

¹estimates for Combi IV/Mono IV based only on the data of the two IV periods.

Discussion

In this study the effect of charcoal co-administration on the pharmacokinetics of moxifloxacin following oral administration and intravenous infusion of a single 400 mg moxifloxacin doses was investigated in a three arm cross over design using intravenous administration as the reference. In vitro data showing complete binding of moxifloxacin to 1 g of activated charcoal suggested that the 40 mg dose recommended for the management of overdose should be sufficient to quantify its effect on the pharmacokinetics of moxifloxacin using the current study design. An additional fourth oral control treatment was not deemed necessary, since moxifloxacin is known to have high oral bioavailability (91%) and all relevant reference data can be obtained from the IV control.

When activated charcoal was co-administered during a 1 h intravenous infusion of 400 mg moxifloxacin, an absolute bioavailability of approximately 80% was obtained. This decrease in exposure can be explained by the adsorption of part of the moxifloxacin dose undergoing gastrointestinal recycling to the activated charcoal, thus preventing subsequent reabsorption. Previous work has shown that activated charcoal also blocks the reabsorption of other quinolones [18–25]. The results from the intravenous treatment arms of this study further support previous preclinical findings suggesting the occurrence of gastrointestinal circulation for moxifloxacin and/or its metabolites [13].

The latter was blocked to the same extent as that for ciprofloxacin reported previously [19]. In view of the longer terminal half-life of moxifloxacin (approximately 12 h vs 4 h for ciprofloxacin) the schedule for the charcoal administration in the present study was designed to maximize its effect on the bioavailability of moxifloxacin. The charcoal administration was timed to cover the period of maximum gastrointestinal turnover of moxifloxacin [28]. In addition, taking into account that moxifloxacin is also secreted into and absorbed from the upper and lower parts of the gastrointestinal tract, the transit time of charcoal should prevent adsorption of moxifloxacin excreted into the gastrointestinal tract for more than 1 day. Since 90% of systemic exposure to the drug occurs within 36 h, only a small portion of the moxifloxacin dose still being excreted into the gastrointestinal tract would not be adsorbed onto activated charcoal. This can be considered as a minor limitation of the present study design. Administration of higher charcoal doses was not considered because of the associated increased risk of gastro-intestinal side-effects (e.g. obstipation). A comparison of the AUC and AUC(0,12 h) ratios in this study underlines this conclusion (see Table 1).

Activated charcoal is a well documented standardized method for the clinical management of overdose with drugs or chemical agents [6]. It can prevent the absorption of almost all drugs present in the gastrointestinal tract independent of their physico-chemical properties with a few exceptions (e.g. ethanol, cyanides). Since its antidotal efficacy is dependent upon on when and for how long it is given after the overdose, it is recommended that activated charcoal is administered as early as possible. Our results illustrate that charcoal may be considered as an option for the management of moxifloxacin overdose. Thus, concomitant administration of 40 g of activated charcoal with 400 mg oral moxifloxacin leads to the almost total prevention of drug absorption.

In humans, oral moxifloxacin is absorbed within 4 h [30], and there is no indication of delayed absorption for doses of up to 800 mg. The present data suggest that doses of charcoal normally used in the management of overdose are adequate for moxifloxacin.

In summary, moxifloxacin was safe and well tolerated when administered as a single intravenous or oral dose alone or in combination with activated charcoal. Our findings indicate that charcoal can be used to manage moxifloxacin overdose, and suggested the occurrence of gastrointestinal circulation of the drug.