Biapenem: Efficacy, Safety and Pharmacokinetics Compared with Meropenem and in Elderly Subjects

Biapenem is a newly developed carbapenem to treat moderate and severe bacterial infections. This multicenter, randomized, parallel-controlled clinical trial was conducted to compare the clinical efficacy, bacterial eradication rates and safety of biapenem and meropenem in the treatment of bacterial lower respiratory tract infections and urinary tract infections (UTIs) at nine centres in China.

Biapenem versus meropenem in the treatment of bacterial infections

Biapenem (1β-methyl-carbapenem) is stable to most β-lactamases, including AmpC and extended-spectrum β-lactamases (ESBLs), with a broad spectrum activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. It combines with penicillin binding proteins and inhibits bacterial cell wall synthesis. Owing to the 1-β-methyl group, biapenem is more stable against the hydrolysis by human renal dehydropeptidase-I (DHP-I) than is meropenem. Thus, in contrast to imipenem and panipenem, which must be compounded with a renal dehydropeptidase inhibitor, biapenem could be administrated independently. Meanwhile, its structure of triazole cations enhances its outer membrane permeability to Gram-negative bacteria. We, therefore, conducted a multicenter, randomized, parallel-controlled clinical trial in nine tertiary care teaching hospitals in China to compare biapenem and meropenem in the treatment of bacterial lower respiratory tract infections and urinary tract infections (UTIs).[1]

Carbapenems are very potent bactericidal drugs to treat severe or complicated bacterial infections and drug-resistant bacterial infections. Biapenem has broad-spectrum antibacterial activity and a rapid bactericidal effect against Gram-positive and Gram-negative organisms in vitro, including anaerobic bacteria and multiple-drug-resistant Pseudomonas aeruginosa. Biapenem is stable against the hydrolysis by human renal DHP-I, and could be administrated independently. Although it has been launched in the Japanese market, it is seldom used outside of Japan, and there is still limited information on the usefulness of this drug. As with meropenem, biapenam belongs to the second generation of carbapenem drugs, with the same action mechanism, similar chemical structure, antimicrobial spectrum and pharmacokinetics. This nine-center, randomized controlled clinical trial confirmed the clinical efficacy, bacterial efficacy and safety of biapenem. The overall clinical efficacy and the overall bacterial eradication rates of biapenem and meropenem were equivalent. The rate of drug-related adverse reactions did not differ significantly in biapenem and meropenem groups. Our clinical trial verified its clinical usage, in accordance with another clinical trial published recently. Our data showed that biapenem was a relatively safe drug. More than a quarter patients had underlying diseases (41 in biapenem group vs. 35 in meropenem group). The occurrence of drug-related adverse reactions was somehow lower in the biapenem group than in the meropenem group, although the difference was not significant.

Pharmacokinetics and Safety of Biapenem

The pharmacokinetics and tolerability of a new parenteral carbapenem antibiotic, biapenem (L-627), were studied in healthy elderly volunteers aged 65 to 74 years (71.6 ± 2.7 years [mean ± standard deviation], n = 5; group B) and ≥75 years (77.8 ± 1.9 years, n = 5; group C), following single intravenous doses (300 and 600 mg), and compared with those of healthy young male volunteers aged 20 to 29 years (23.0 ± 3.5 years, n = 5; group A). The agent was well tolerated in all three age groups. Serial blood and urine samples were analyzed for biapenem to obtain key pharmacokinetic parameters by both two-compartment model-dependent and -independent methods. The maximum plasma concentration and area under plasma concentration-versus-time curve (AUC) increased in proportion to the dose in all three groups. Statistically significant age-related effects for AUC, total body clearance, and renal clearance (CLR) were found, while elimination half-life (t1/2β) and percent cumulative recovery from urine of unchanged drug (% UR) remained unaltered (t1/2β, 1.51 ± 0.42 [300 mg] and 2.19 ± 0.64 [600 mg] h [group A], 1.82 ± 1.14 and 1.45 ± 0.36 h [group B], and 1.75 ± 0.23 and 1.59 ± 0.18 h [group C]; %UR, 52.6% ± 3.0% [300 mg] and 53.1% ± 5.1% [600 mg] [group A], 46.7% ± 7.4% and 53.0% ± 4.8% [group B], and 50.1% ± 5.2% and 47.1% ± 7.6% [group C]).[2]

A significant linear correlation was observed between the CLR of biapenem and creatinine clearance at the dose of 300 mg but not at 600 mg. The steady-state volume of distribution tended to be decreased with age, although not significantly. Therefore, the age-related changes in parameters of biapenem described above were attributable to the combination of decreased lean body mass and lowered renal function of the elderly subjects. However, the magnitude of those changes does not necessitate dosage adjustment in elderly patients with normal renal function for their age. As internal standards, 5-hydroxyindole-3-acetic acid and o-nitroacetanilide were used for plasma and urine samples, respectively. For plasma, the calibration curve was generated by measuring the plasma solution with the biapenem concentrations adjusted to 2.0, 4.9, 9.9, 19.7, 49.3, and 98.5 μg/ml. The calibration curve thus obtained was linear in this concentration range (r = 0.9998). Its coefficient of variation (CV) was 1.38%. The mean recovery (n = 6) of biapenem was 99.5%. The detection limit was 0.1 μg/ml in plasma. For urine, the calibration curve was generated by measuring the urine solution with the biapenem concentrations adjusted to 20.0, 50.1, 100.2, 200.4, 501.0, and 1,002.0 μg/ml. The calibration curve thus obtained was linear in this concentration range (r = 0.9999). The CV was 2.44%. The mean recovery (n = 6) of biapenem was 102.5%. The detection limit was 1.0 μg/ml in urine. When a β-lactam antibiotic is prescribed for an elderly patient, precautions should be taken with regard to age-related changes in pharmacokinetic properties. However, in consideration of the safety and tolerance profiles of β-lactam antibiotics including carbapenem, the magnitude of age-related changes observed in the pharmacokinetics of biapenem does not necessitate dosage adjustment in elderly patients with renal function normal for their age.

References

[1]Wang X, Zhang X, Zong Z, Yu R, Lv X, Xin J, Tong C, Hao Q, Qin Z, Xiong Y, Liu H, Ding G, Hu C; Biapenem Study Collaborative Group. Biapenem versus meropenem in the treatment of bacterial infections: a multicenter, randomized, controlled clinical trial. Indian J Med Res. 2013 Dec;138(6):995-1002. PMID: 24521647; PMCID: PMC3978993.

[2]Kozawa O, Uematsu T, Matsuno H, Niwa M, Takiguchi Y, Matsumoto S, Minamoto M, Niida Y, Yokokawa M, Nagashima S, Kanamaru M. Pharmacokinetics and safety of a new parenteral carbapenem antibiotic, biapenem (L-627), in elderly subjects. Antimicrob Agents Chemother. 1998 Jun;42(6):1433-6. doi: 10.1128/AAC.42.6.1433. PMID: 9624490; PMCID: PMC105618.

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