AbstractObjectives

: To evaluate the pharmacokinetic (PK) parameters of the 2020 WHO-recommended pediatric dosage of levofloxacin and a higher than WHO dosage.

Methods

: Children aged 1 to 15 years old with tuberculosis who received levofloxacin-based treatment for at least seven days were enrolled. Firstly, five children were enrolled to receive the WHO-recommended dosage (15-20 mg/kg/day) then an additional five children received a higher than WHO dosage (20-30 mg/kg/day). Blood samples were collected at pre-dose and post-dose 1, 2, 4, 6, 8, and 12 hours. A target of the ratio of the free area under the concentration-time curve to minimum inhibitory concentration ratio (fAUC/MIC) was 100.

Results

: The median (IQR) age was 9.6 (4.9-10.5) and 12.0 (10.1-12.3) years old in the WHO dosage and the higher than WHO dosage groups, respectively. The median (IQR) duration of anti-TB treatment was 24 (8-24) weeks. The geometric mean (95% confidence interval, 95%CI) of fAUC/MIC was 60.4 (43.5-84.0) and 103.2 (70.1-151.8) in the WHO- and higher than WHO dosage groups, respectively. There was no adverse event of QT prolongation or any other grade 3 or 4 adverse events.

Conclusions

: Levofloxacin at higher dose of 20-30 mg/kg/day could achieve the fAUC/MIC target in children.

Keywords

Background

Tuberculosis in children may result in significant morbidity and mortality. From 2018 to 2020, the World Health Organization (WHO) estimated that 1.4 million children were treated for tuberculosis, and only 12,200 children were treated for multidrug-resistant tuberculosis (MDR-TB) which is lower than set targets (World Health Organization, 2021). The incidence of isoniazid-resistant tuberculosis (Hr-TB) in children with tuberculosis was estimated to be 12% in 2010, that is 100,000 incident cases of Hr-TB globally (Yuen et.al., 2015). Levofloxacin, which is a bactericidal drug against Mycobacterium tuberculosis, has been used as a second-line medication in treatment regimens for children with drug-resistant tuberculosis (DR-TB), including Hr-TB and MDR-TB and in children who were intolerant to the first-line anti-tuberculosis medications. Additionally, levofloxacin has been proposed for preventive therapy in contacts of infectious MDR-TB patients. (World Health Organization, 2020a, 2020b).

As the bactericidal activities of fluoroquinolones are concentration-dependent, the free area under the concentration-time curve (fAUC) is considered as the pharmacokinetic (PK) parameter most closely correlated with the efficacy. The optimal efficacy of levofloxacin has been shown to be predicted by a target of fAUC0-24/MIC ≥100-146 mg.h/L in several studies. (Van't Boveneind-Vrubleuskaya et.al., 2017; Deshpande et.al., 2019) However, the actual minimum inhibitory concentration (MIC) values of levofloxacin against M. tuberculosis are not readily available, and the WHO recommends a breakpoint of 1 mg/L for levofloxacin. A study in Thailand reported that MICs of drug-susceptible M. tuberculosis and the MDR M. tuberculosis isolation were 0.5 and 1 mg/L, respectively. (Niward et.al., 2016; Pracharktam et.al., 2001)

In 2014, the WHO DR-TB treatment guideline recommended a body weight-based dosage of 15 to 20 mg/kg/day for children aged under five years old and 10 to 15 mg/kg/day for older children. (World Health Organization, 2014) However, several studies reported low concentrations of levofloxacin in older children, which raised concerns regarding the development of drug resistance. (Mase et;al, 2016; Thee et.al., 2014; Savic et.al., 2015; Malik et.al., 2019) In 2020, the WHO recommended a revised levofloxacin dosage for prevention and treatment in children aged under 15 years old as 15 to 20 mg/kg/day. However, the studies from South Africa reported sub-optimal exposure of levofloxacin, at the AUC0-24 of 25.4 - 40.8 mg.h/L, in children who received a dosage of 15-20 mg/kg/day and thus recommended a higher dosage of levofloxacin (in a tablet preparation) to be 18-40 mg/kg/day. (Thee et.al., 2014; Denti et.al., 2018)

Our study aimed to evaluate the pharmacokinetics, safety, and tolerability of the 2020 WHO-recommended dosage (15-20 mg/kg/day) and a higher than WHO dosage (20-30 mg/kg/day) of levofloxacin in children with tuberculosis.

Results

Patient demographics

From 2019 to 2021, 10 children were enrolled in the study, 5 children were in the WHO-recommended dosage group (WHO dosage group), and 5 in the higher than WHO-recommended dosage group (higher than WHO dosage group). The median (IQR) of age, body weight, and GFR were 9.6 (4.9-10.5) years, 28 (19-28) kg, and 132.5 (128.3-132.5) ml/min/1.73 m2, respectively in the WHO dosage group and 12.0 (10.1-12.3) years, 32 (28-32) kg and 109.6 (107.7-118.4) ml/min/1.73 m2, respectively in the higher than WHO dosage group. Patient characteristics and treatment regimens are provided in Table 1 and Supplement Table 1. As of February 2022, all children in the WHO dosage group and four of five children in the higher than WHO dosage group completed the treatment regimen. One case (No.9) in the higher than WHO dosage group has been planned for extended treatment to 16 months period due to rifampicin allergy. One case (No.6) in the higher than WHO dosage group was lost to follow up after 8 weeks of treatment initiation. The other cases had favorable outcomes after treatment completion.

Table 1Demographic data of children in the WHO dosage group and the higher than WHO dosage group

Abbreviations: IQR = Interquartile range, BMI = Body mass index, and GFR = Glomerular filtration rate

Pharmacokinetic analysis

The PK parameter and plasma concentration-time profiles of levofloxacin in both groups are shown in Table 2, Supplement Table 2, and Figure 1. During the years 2019 and 2020, five children were enrolled into the WHO dosage group of levofloxacin with a median (IQR) dosage was 18 (17-18) mg/kg/day. Two children aged under 5 years old took ground tablets. The median (IQR) duration receiving levofloxacin on the PK days was 12 (11-13) days after treatment initiation. The geometric mean (95% confidence interval; 95%CI) of Cmax, AUC0-24, Vd, CL were 10.3 (7.3-15.1) mg/L, 80.6 (58.0-112.0) mg.h/L, 30.6 (14.2-66.2) L, and 4.6 (2.3-9.0) L/h respectively. The geometric mean (95%CI) fAUC/MIC, calculated using a protein unbound fraction of 0.75 and MIC 1 mg/L, was 60.4 (43.5-84.0). No children in this group could achieve the target fAUC/MIC. However, if the MIC was 0.5 mg/L, all except one in the WHO dosage group achieved the targeted fAUC0-24/MIC >100.

Table 2Pharmacokinetic parameters of levofloxacin in the WHO dosage group and the higher than WHO dosage group.

Abbreviations: GM = Geometric mean, 95%CI = 95% confidence interval, Tmax = the time to Cmax, Cmax = the maximum plasma concentration, MIC = minimum inhibitory concentration, and AUC = the area under the concentration-time curve

Figure 1Plasma concentration-time profiles of levofloxacin observed from individuals at the steady-state: the WHO dosage group 15-20 mg/kg/day orally once daily (n = 5) and the higher WHO dosage group 20–30 mg/kg/day orally once daily (n = 5).

Next, during the years 2020 and 2021, five children were enrolled into the higher than WHO dosage group with the median (IQR) dosage was 25 (24-26) mg/kg/day. The median (IQR) of the interval period of PK Day following treatment initiation was 9 (7-10) days. The geometric mean (95%CI) of Cmax, AUC0-24, Vd, CL were 16.7 (10.3-27.1) mg/L, 137.6 (93.5-202.4) mg.h/L, 44.3 (27.2-71.9) L, and 5.2 (3.1-8.9) L/h, respectively. The geometric mean (95%CI) fAUC/MIC, calculated using a protein unbound fraction of 0.75 and MIC 1 mg/L, was 103.2 (70.1-151.8). In this group, two children could achieve the target fAUC/MIC, and a further two almost reached the target. However, if the MIC was 0.5 mg/L, all children achieved the targeted fAUC0-24/MIC >100.

Safety and tolerability

The median (IQR) of the duration of the levofloxacin-based regimen was 24 (24-48) weeks and 12 (8-24) weeks in the WHO dosage group and the higher than WHO dosage group as of February 2022, respectively. Five children (one child in the WHO dosage group and four children in the higher than WHO dosage group) had adverse events which were possibly related to levofloxacin, including nausea (grade 1), vomiting (grade 1-2), myalgia (grade 1), arthralgia (grade 1), headache (grade 1), irritability (grade1) and difficulty sleeping (grade 1). All adverse events were reported in the first two weeks and were resolved over time. One child (No.6) took a dosage of levofloxacin 30 mg/kg/day and subsequently reported myalgia, headache, nausea, and vomiting (grade1-2), which were mild and did not disturb her regular activities. All symptoms were resolved after two weeks.

No children had grade 3 and 4 adverse events, and none had to discontinue levofloxacin because of drug-related adverse events. Additionally, no QTc prolongation (QTcF >450 msec) was observed during the whole treatment course. The median (IQR) QTcF was 388 (363-388) msec at baseline, 403 (350-413) msec at the PK study day, and 400 (397-413) msec at 4 weeks after treatment in the WHO dosage group. Likewise, the median (IQR) QTcF was 388 (372-388) msec, 384 (343-395) msec, and 390 (387-411) msec at baseline, PK study day and 4 weeks after treatment, respectively in the higher than WHO dosage group. The median (IQR) alanine aminotransferase (ALT) at PK study day was 10 (8-13) U/L and 12 (12-14) U/L in the WHO dosage group and the higher than WHO dosage group, respectively, and was still within the normal range during the entire period of the treatment course.

Discussion

In this study, we observed that children with the WHO-recommended levofloxacin dosage of 15 to 20 mg/kg/day had a fAUC0-24/MIC below the reference target of 100, increasing the risk poor clinical outcomes. (Van't Boveneind-Vrubleuskaya et.al., 2017; Cegielski et.al., 2014; Srivastava et.al., 2011) On the contrary, most children with the higher levofloxacin dosage of 20 to 30 mg/kg/day had achieved the target AUC without any severe adverse events. Therefore, we proposed to have the study of a higher dosage regimen of levofloxacin for tuberculosis treatment in a larger sample population involving different age ranges to determine the optimal dosage.

In 2014, the WHO DR-TB treatment guideline recommended a weight-based dosage of 15 to 20 mg/kg for children aged under five years and 10 to 15 mg/kg for older children. (Thee et.al., 2014) However, Malik et al. reported that most children aged more than five years did not achieve optimal drug exposure and suggested an increased dosage of levofloxacin to be nearly 30 mg/kg. (Malik et.al., 2019) In 2020, the WHO recommended the levofloxacin dosage for children aged under 15 years old regarding the body weight: 15 to 20 mg/kg if the body weight of 5 to 34 kg; 750 mg if the body weight of 35-45 kg; and 1,000 mg if the body weight of more than 45 kg. However, consistent with our study, several studies observed that most children with this recommended dosage still had lower than the targeted PK concentration. Kumar et al. reported that 42% of the children aged 5-18 years old with 20 mg/kg/day of levofloxacin had the PK parameters of levofloxacin below the Cmax target level. (Kumar et.al., 2018) Denti et al. suggested increasing the levofloxacin dosage to18 to 40 mg/kg/day to the equivalent adult dosage level of 750-mg daily. (Denti et.al., 2018) Savic et al. analyzed a pediatric population PK model and suggested an oral levofloxacin dosage of 19 to 33 mg/kg to achieve the target PK level. (Savic et.al., 2015) Here, we reported that the levofloxacin dosage of 20 to 30 mg/kg achieved the fAUC0-24/MIC target. We found that increasing the dosage of levofloxacin leads to an increased levofloxacin Cmax and AUC0-24, as reported in the adult population, reflecting the linear pharmacokinetics of levofloxacin. (Peloquin et.al., 2018) Additionally, as levofloxacin was mainly excreted renally, with a renal clearance of approximately 99 ml/min, the drug exposure in patient who was on the similar dosage with lower GFR was likely to be higher than others as reported in the Supplement tables 1 and 2. (Chien et.al., 1998)

The fAUC/MIC is a significant PK parameter to predict the maximal microbial kill and the suppression of acquired drug resistance. Van't Boveneind-Vrubleuskaya et al. reported that the target fAUC0-24/MIC >100 predicted the preferable efficacy of levofloxacin. However, Deshpande et al. revealed that AUC0-24/MIC of 146 was associated with maximal M. tuberculosis kill, and of 360 with the suppression of resistance. (Van't Boveneind-Vrubleuskaya et.al., 2017; Deshpande et.al., 2019) The resistance to fluoroquinolones was assumed to be uncommon in our population of mainly HrTB participants, compared to the previous report. Consequently, the MIC should be lower than the WHO-recommend breakpoint of levofloxacin of 1 mg/ml. (Niward et.al., 2016) However, the previous study in Thailand reported the MIC values for DS-TB cases to be 0.5 mg/L and of the MDR-TB cases to be higher at 1 mg/L. (Pracharktam et.al., 2001) Therefore, the MIC at 1.0 mg/ml was adopted for the target fAUC0-24/MIC for treating Hr-TB or MDR-TB children in our study. Of note, if the MIC was set at 0.5 mg/mL, all except one in the WHO dosage group achieved the target fAUC0-24/MIC >100.

In terms of safety concerns, fluoroquinolones had some reported adverse effects on the musculoskeletal, central nervous, and cardiovascular systems. (Patel et.al., 2016) In this study, we reported adverse effects including arthralgia, myalgia, headache, and insomnia grade 1-2, which were resolved within two weeks, similar to other studies. (Garcia-Prats,et.al., 2019; Noel et.al., 2007) Garcia-Prats et al. monitored the safety of long-term levofloxacin in young children with the median observation period of 12 months and reported only a few musculoskeletal events such as pain and arthralgia, which were mild and self-limited. (Garcia-Prats et.al., 2018) In this study, no children had a QTcF >450 msec, and a maximum change from baseline was 78 msec. Similar to a previous study, there was no QTc prolongation observed in children receiving fluoroquinolones. (Garcia-Prats et.al., 2018) Still, careful safety monitoring in children with a higher dosage than 20 mg/kg/day is mandatory, as other medications causing QT-interval prolonging such as clofazimine, bedaquiline, and delamanid may be include in the DR-TB regimens.

Our study was limited by a small sample population with no children aged lower than 5 years old in the higher than WHO dosage group. Younger children reported a high clearance rate almost twice the rate than in adults; therefore, increased dosages in this population are unlikely to be overdosage. (Thee et.al., 2014) Furthermore, two children in this study took ground tablets which may interfere with the drug bioavailability; though, a previous study reported no effect on the bioavailability of levofloxacin in a ground tablet. (Denti et.al., 2018) Recently, a novel 100 mg dispersible levofloxacin tablets became available with better bioavailability. (Garcia-Prats,et.al., 2019) Notably, other medications in the tuberculosis regimen may also contribute to the reported adverse events. Finally, as the actual MIC values are not readily available, the WHO recommended breakpoint for levofloxacin as MIC of 1 mg/L was adopted in the calculation of a target fAUC/MIC in this study. Further PK and safety studies of the higher than WHO dosage of levofloxacin, particularly in children of different ages, are suggested.

Materials and Methods

Study design

A prospective, open-label, dosage-ranging pharmacokinetic pilot study (Clinical trial registration number: TCTR20190515001) was conducted at King Chulalongkorn Memorial Hospital and Queen Sirikit National Institutes of Child Health, Bangkok, Thailand. Inclusion criteria were 1) children diagnosed with tuberculosis either by the molecular techniques (reverse transcriptase-polymerase chain reaction (RT-PCR) for M. tuberculosis complex, or Xpert MTB/RIF) or by mycobacterial culture, 2) aged 1 to15 years old, 3) had body weight from 6 to 40 kg and 4) received levofloxacin for tuberculosis treatment. The exclusion criteria included 1) a history of levofloxacin allergy, 2) a known case of levofloxacin-resistant tuberculosis, 3) a history of QT prolongation, and 4) pregnancy.

The children were discontinued from the study if the children 1) were intolerant to levofloxacin, 2) had adverse effects of clinical symptoms or laboratory abnormalities grade 3-4 as for the grading score for the severity of Adult and Pediatric Adverse Events by Division of AIDS (DAIDS) (Division of AIDS, 2017), or 3) had an electrocardiogram (ECG) finding of prolonged QTc as defined by the Fridericia formula (QTcF) interval >450 msec. (Fridericia, 2003)

Levofloxacin dosing and administration

The study was conducted as two consecutive cohorts. The first cohort adopted the 2020-WHO levofloxacin dosage of 15 to 20 mg/kg/day once daily. The safety and PK parameters were evaluated as per study protocol. Once 4 of 5 participants in the study cohort 1 revealed no adverse events at grade 3 and 4 and did not achieve the targeted fAUC0-24/MIC (> 100), the second cohort was opened. Study cohort 2, using the higher than WHO levofloxacin dosage (20 to 30 mg/kg/day once daily), was initiated with approval from the external Data Safety Monitoring Board (DSMB); including a pediatrician, a pharmacist, and a statistician. Levofloxacin 100 mg or 500 mg tablets (Siam Pharmaceuticals Co. Ltd., Bangkok, Thailand.) were prescribed as a whole tablet in older children and a ground tablet with water for younger children. Of note, levofloxacin is recommended to administer two hours before or four hours after ingesting milk-based products, antacids, or other medications containing divalent cations (iron, magnesium, calcium, zinc, vitamins). In addition, the on-site investigators selected other medications in the tuberculosis treatment regimen based on the standard treatment guidelines. Before the PK study day, children took medications in the morning, and on the PK study day, levofloxacin was administered during fasting by the study team at the same time as the day before.

Blood sampling and treatment monitoring

After achieving steady-state, defined as at least seven days after levofloxacin initiation, blood samples (2 mL) were collected at 0 (as pre-dose), 1, 2, 4, 6, 8, and 12 h (as post-dose). A blood sample was collected by using a single catheter if possible; however, if it was clotted, a new catheter was inserted in place. Whole blood samples were centrifuged to obtain the plasma samples with an aliquot of 500 μl to be stored at -80° Celsius until analysis.

Safety and tolerability

Safety and tolerability were assessed by adverse event monitoring using a 14-day reported diary of adverse events, physical examination, clinical laboratory evaluation, and ECG. Participants were monitored via telephone on day 3 after initiation and then follow-up at the clinic at day 7-14 (PK study day), week 4, 8, 12 and then every 12 weeks until completing the treatment course. Blood chemistry including creatinine and ALT was analyzed at baseline, day 7-14 (PK study day), and week 12. Glomerular filtration rate (GFR) was calculated using the modified Schwartz formula. ECG was performed at baseline, day 7-14 (PK Day), 4 and 12 weeks of the treatment, and then every 3 months until the completion of the treatment course and the QTcF was calculated by a pediatric cardiologist. On the PK study day, the ECGs were performed at 3 hours post dose.

Determination of levofloxacin plasma concentration

Plasma levofloxacin concentrations were analyzed at the Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Department of Pharmacology, Faculty of Medicine, Chulalongkorn University using a modified and validated high-performance liquid chromatography (HPLC) assay with fluorescence method of Czyrski and Szlek. (Czyrski et.al., 2016) In brief, levofloxacin chromatographic separation was performed by a reversed-phase HPLC, using a Luna 5u C18 column (250 mm×4.6 mm, 5 microns (Phenomenex, USA). Sample purification was done by using protein precipitation. The analytes were eluted under isocratic conditions using a mobile phase composed of acetonitrile and 0.4% triethylamine (TEA) at pH 4. The runtime was 13 minutes. A linear calibration curve of the concentrations ranged from 0.1–100 μg/mL for plasma concentrations of levofloxacin was performed with r2 >0.999. Intra- and inter-day precisions of levofloxacin concentrations (0.3, 37.5 and 75 µg/mL) were 0.41–8.37% and 1.54–11.16%, respectively. The accuracy of the technique was 86.63–103.71%. The mean absolute recovery of levofloxacin of all three analytes was more than 92.21%.

Data and Pharmacokinetic analysis

For patient demographic data, the median with interquartile ranges (IQR) were analyzed for continuous variables and the percentage for categorical variables. Comparison of continuous variables was tested with a Wilcoxon rank-sum test and geometric means were compared using a two-independent t-test. The PK parameters were calculated using the non-compartmental analysis by Phoenix WinNonlin version 8.3.4 (Pharsight Corp., Mountain View, CA, USA). The maximum plasma concentration (Cmax), the time to Cmax (Tmax), the area under the plasma concentration-time curve from 0–24 h (AUC0–24), the volume of distribution (Vd), half-life (t1/2), and the clearance (CL) were reported as the median (IQR) or Geometric mean (95%CI). In this case, the concentration of levofloxacin at 24 hours after oral administration was estimated to be equivalent to its concentration before the dosage administration as the samples were obtained at a steady state.

The fAUC in the fAUC/MIC, as a predictor for the efficacy of levofloxacin tuberculosis treatment, was calculated by multiplying AUC0-24 by (100% minus the published values of protein binding levofloxacin percentages; 25%). (Peloquin et.al., 2008) Since the actual MIC values are not readily available, fMIC/MIC was calculated using the MICsof 1 and 0.5 mg/L.

Conclusion

The WHO-recommended dosage of levofloxacin in children with tuberculosis was suboptimal to achieve the targeted exposure. Higher levofloxacin dosage (20-30 mg/kg/day) was proposed to achieve an optimal drug exposure with tolerable adverse events and reduce the risk of drug resistance.

Acknowledgements

We thank the patients and their families who participated in this study, the Drug Safety Monitoring Board (DSMB) –Prof Pope Kosalaraksa (Pediatric infectious Disease specialist, Faculty of Medicine Khon Kaen University), Assoc Prof Thitima Wattanavijitkul (Pharmacist, Faculty of Pharmacy, Chulalongkorn University, Stephen Kerr (Statistician, Thai Red Cross AIDS research center); Dr Sarin Lekchuensakul (Cardiologist, King Chulalongkorn Memorial Hospital), Dr Susama Chokesuwattanaskul (English editing) and the study team.

Author Contributions:

Study design: W.J., P.C., and T.P., Data collection: W.J., J.M., M.T., P.S., P.SNA, and W.P.; Data analysis: W.J. and N.W.; Investigation: W.J., Writing—original draft preparation, W.J., and N.W; Writing—review and editing: T.S., P.C., and T.P.

Funding: Health System Research Institute, Thailand, Grant number 62-015 and 63-139

Ethical review: This study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (IRB No. 607/61) and the Queen Sirikit National Institute of Child Health (IRB 7346). Written informed consents were obtained from the parents, and the children aged ≥7 years were asked to provide assent if appropriate.

Conflict of interest

We have no conflicts of interest to declare.

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Appendix. Supplementary materialsArticle InfoPublication History

Accepted: July 8, 2022

Received in revised form: July 7, 2022

Received: June 1, 2022

Publication stageIn Press Journal Pre-ProofFootnotes

Clinical trial registration: TCTR20190515001

Identification

DOI: https://doi.org/10.1016/j.ijid.2022.07.029

Copyright

© 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

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