PK/PD analysis of biapenem in patients undergoing continuous hemodiafiltration

In this study, we investigated the PK of BIPM using compartmental and non-compartmental
analysis in patients undergoing CHDF who had various levels of renal function, and
examined the suitability of various administration regimens in terms of PK/PD breakpoint
for various bacteria, by means of Monte Carlo simulation.

Ikawa et al. analyzed time courses of BIPM concentration in plasma and FD after single
administration in renal failure patients undergoing CHDF 18]. Here, we aimed to obtain a model to analyze the results of repeated administration
of BIPM in patients undergoing CHDF who retained various levels of renal function.
Time courses of BIPM concentration in plasma and FD in patients undergoing CHDF closely
fitted the observed values, suggesting that the constructed model formula successfully
represents the results of repeated administration of BIPM in patients undergoing CHDF.
In the present study, SC (indicating penetration from blood to dialyzer) was almost
1.0 for the PS membrane material, which is almost the same as the value for PMMA membrane
18], 24]. Thus, there appears to be essentially no difference between PS and PMMA membranes
in regard to drug penetration 18]. These results seem consistent with the characteristics of BIPM, such as low molecular
weight and low protein binding rate.

We found a strong correlation between the sum of CL
_non-CHDF
and CL
_CHDF
obtained by compartmental analysis and total clearance obtained by non-compartmental
analysis (r ²
?=?1.00), indicating that the compartment model formula was appropriate. Ikawa et
al. reported that CL
_CHDF
(1.29?±?0.08 L/h) was almost the same as the sum of Q
_F
and Q
_D
(1.4 L/h) in CHDF with a PMMA membrane 18]. Suyama et al. also reported that CL
_CHDF
(1.28?±?0.14 L/h) was almost the same as the sum of Q
_F
and Q
_D
(1.4 L/h) in CHDF with a PMMA membrane 24]. In this study, CL
_CHDF
(1.5?±?0.1 L/h) estimated by compartmental analysis was similar to the sum of Q
_F
and Q
_D
(1.5–1.7 L/h) in CHDF with a PS membrane. Considering the SC estimated by non-compartmental
analysis, CL
_CHDF
of BIPM would be determined by the sum of dialysate flow rate and filtration flow
rate. On the other hand, CL
_non-CHDF
represents the sum of non-renal clearance and residual renal clearance. Metabolism
of BIPM in kidney and other tissues would contribute to CL
_non-CHDF
. Nakajima et al. detected two DHP-1 metabolites of BIPM, L-cysteine and L-cystine,
in urine, and reported that excretion of urinary metabolites accounted for approximately
15 % of total clearance; these metabolites were not detected in plasma, suggesting
that metabolism of BIPM in kidney contributes to residual renal clearance 19]. DHP-1 is also expressed in the ascending colon and ileum as well as the kidney,
and the activity of DHP-1 in ileum has been reported to be twice that in kidney, suggesting
that non-renal DHP-1 function in ileum would also contribute to non-renal clearance
25]. The relationship between GFR calculated before CHDF application and CL
_non-CHDF
was given by y?=?1.86 x?+?1.02 (r ²
?=?0.97) (Fig. 3), and the y-intercept (1.02 L/h) represents non-renal clearance. Non-renal clearance
in healthy adults can be estimated as approximately 3.23 L/h, using reported values
of total clearance of BIPM in healthy adults of 12.9?±?1.2 L/h, and urinary excretion
rates of unchanged and changed BIPM of approximately 60 and 15 %, respectively 19]. Nagashima et al. reported that non-renal clearance was 2.60?±?1.55 L/h in patients
with renal failure during dialysis with a PS membrane, while CL
_tot
in patients was 2.62?±?0.60 L/h without HD, so that CL
_tot
was the same as non-renal clearance in patients with renal failure 17]. Non-renal clearance in the present study was a half to one-third of those values.
After extracting patients with sepsis from Fig. 3, the y-intercept took a negative value (data not shown), indicating that non-renal
clearance would be almost zero in patients with sepsis. In sepsis, hepatic clearance
and renal clearance would be diminished owing to the reduced function of systemic
organs and impaired blood flow 26], leading to loss of DHP-1 activity in the kidney and other organs. Thus, we consider
that the reason why average non-renal clearance in this study was lower than in previous
studies is the low values in patients with sepsis.

We investigated the variation in % of T??MIC based on the average values of the PK
parameters obtained by compartmental analysis for different regimens, including dose,
dosing interval, infusion time, and CHDF conditions applied in our hospital. The %
of T??MIC
_{4 ?g/mL}
was more than 40 % in all regimens of 900 mg or more daily dose, regardless of the
CHDF conditions and infusion time. Ikawa et al. also reported that although the regimen
of 300 mg every 12 h failed to achieve T??MIC
_{4 ?g/mL}
of more than 40 %, the regimen of 600 mg every 12 h did do so 18]. These results indicate that the minimum dosage regimen required to achieve T??MIC
_{4 ?g/mL}
of more than 40 % is 300 mg every 8 h (total amount: 900 mg). On the other hand, no
regimen gave % of T??MIC
_{8 ?g/mL}
of more than 40 %, suggesting that these regimens could not achieve the maximal kill
end point. However, since the % of T??MIC values obtained using average PK parameters
do not reflect variations of CL
_non-CHDF
associated with partial kidney function, these values may not be adequate as a clinical
indicator.

Monte Carlo simulation is a computer modeling process that incorporates variability
in pharmacokinetic parameters and the natural MIC distribution within a bacterial
population. It can be used to develop interpretive susceptibility criteria based on
PK/PD breakpoints 27]. In this study, Monte Carlo simulations with 10,000 cases were performed to examine
PK/PD breakpoint using the mean and variance of the PK parameters. As regards infusion
time, the PK/PD breakpoint obtained for all regimens with 1 h infusion was higher
than that for 0.5 h infusion, suggesting that the 1 h infusion provides a better outcome.
In this study, the highest PK/PD breakpoint (over 80 % PTA) was 2 ?g/mL with 300 mg
every 8 h, 300 mg every 6 h, and 600 mg every 12 h, indicating that these regimens
provide a sufficient bactericidal effect in the case of bacteria with MIC
_{2 ?g/mL}
, but not MIC
_{4 ?g/mL}
. In order to obtain an antimicrobial effect of BIPM towards high MIC bacteria (more
than 4 ?g/mL), such as Pseudomonas aeruginosa, higher dose administration and an appropriate regimen would be needed, although
the maximum permitted dose of BIPM in Japan has been set at 1,200 mg/day. Among the
regimens examined in this study, 300 mg every 6 h with infusion for 1 h was the optimal
regimen, and PTA at MIC
_{2 ?g/mL}
was 90.2 %. Although maximum MIC more than 80 % is adopted as the PK/PD breakpoint
in Japan, most other countries define it as more than 90 % 27], so the regimen of 300 mg every 6 h with infusion for 1 h also meets the international
standard for MIC
_{2 ?g/mL}
bacteria. Although the PK/PD breakpoint is expected to become a decision criterion
for individualized and optimized antibacterial therapy, it is focused primarily on
the antibacterial agent. In the future, it will be important to take bacterial character
into account as well, for example, by means of antimicrobial susceptibility testing
and identification of the causative bacteria of infectious diseases.

The present study has several limitations. Firstly, we performed the Monte Carlo simulation
using the mean and variance of the PK parameters obtained with the standard two-stage
method because of the small number of cases (total, 7 cases), and this might have
resulted in overestimation of the inter-individual variation compared to population
pharmacokinetics analysis, such as nonlinear mixed effects modelling (NONMEM®). Further,
we did not include a parameter of renal function (e.g. GFR or creatinine clearance)
in the Monte Carlo simulation, even though BIPM clearance is correlated with renal
function. Therefore, as a next step, it would be desirable to identify the PK/PD breakpoint
more precisely in patients undergoing CHDF by means of Monte Carlo simulation of BIPM
using population pharmacokinetic parameters including renal function (e.g. GFR and
creatinine clearance), based on larger numbers of patients with various levels of
renal function. In addition, from the viewpoint of clinical applicability, we did
not establish that the optimal regimen (300 mg every 6 h with infusion for 1 h) determined
by Monte Carlo simulation is safe, because only one patient received the optimal regimen
in this study. Therefore, it is impossible to evaluate the safety of optimal regimen.
However, the simulated maximum steady-state plasma concentration with the optimal
regimen in the present study was approximately 11–24 ?g/mL. This concentration is
lower than the maximum steady-state plasma concentration after administration of 600 mg
by 1 h infusion every 12 h in healthy adults (32.4?±?2.32 ?g/mL) 19]. Therefore, it seems likely that the optimal regimen would be safe even in renal
dysfunction patients undergoing CHDF. Nevertheless, it will be important to confirm
the safety of the optimal regimen, and clinicians should carefully consider the appropriate
regimen when administering BIPM to renal dysfunction patients undergoing CHDF, in
addition to monitoring for side effects.