11.1.1. Dosing

Doses are grouped by Standard of Care (SOC) IV doses, Study IV doses and Study PO doses in Table 14.2.1.1 (IV doses) and Table 14.2.1.2 (PO doses). All participants were receiving SOC IV clindamycin at study enrollment. Sites entered a maximum of 6 SOC doses administered prior to the first dose of study drug and all study drug doses administered during the study period (Days 1-14). Doses in this section are presented in mg and mg per kg of participant’s dosing weight.

There were 85 IV SOC doses reported in the 22 participants with a median (range) of 3.5 (1-6) doses per participant. This includes 2 SOC doses used for the PK sampling, an option that was added with Version 6 of the protocol. The median SOC dose was 675 (216-1050) mg. Younger children (2 - <12 years age stratum) had a median dose of 532 (300-780) mg and older children had a median dose of 763 (216 – 1050) mg. Dose per kg of participant dosing weight was similar in all age/BMI strata with median doses of 10.8 mg/kg and 10.0 mg/kg for BMI <95^th percentile and BMI ≥95^th percentile respectively in the younger age stratum and 10.0 mg/kg and 9.2 mg/kg for BMI <95^th percentile and BMI ≥95^th percentile respectively in the older age stratum. Doses were scheduled every 8 hours for 72% of the doses and every 6 hours for 27% of the doses. One participant’s first SOC dose was partial because the IV infiltrated during infusion.

One hundred ten study doses were reported in the IV portion of the study with a median of 3 study doses per participant (range 2 – 26). Median study dose was 900 (300-1100) mg; children in the younger age stratum had a median dose of 501 mg and children in the older age strata had a median dose of 900 mg. Median dose per kg of participant dosing weight was 10.0 (3.0-14.3) mg/kg overall and for each strata except 2- <12 years/BMI <95^th percentile group which had a median of 13.3 mg/kg. Eighty-six percent of the doses were administered every 8 hours and 14% were administered every 6 hours.

One participant [▬] continued into the PO portion of the study. This participant received 13 PO doses of 300 mg (or 1.3 mg/kg) each, every eight hours. When the participant returned to provide PO PK samples, a review of the dosing diary found that the child did not take the PO doses as instructed and PO PK samples were not collected.

11.1.2. PK Sampling

Twenty-one participants had at least 1 fresh plasma sample and are included in Table 14.2.2.1, Summary of PK Sampling. Ninety-one samples, all on IV doses, were collected during this study with a median (range) of 4 (1-6) PK samples per participant. The 91 samples consisted of 89 timed fresh plasma samples and 2 scavenged plasma samples.

Table 11-1 shows how the 91 collected samples fit into the planned PK sampling schedule. Ninety-six percent (87/91) of the collected samples were during planned sampling times.

Table 11-1

PK Scheduled Sampling Times and PK Samples (PK Population).

As noted above, there were no PO dosing PK samples collected for this study.

11.1.3. PK Drug Concentration

Clindamycin was measured in each sample. Descriptive summary statistics of concentration values (ng/mL) are reported in Table 14.2.3.1. The 89 fresh plasma samples had a median (range) concentration of 6.4 (0.3 – 24.6) ng/mL. The 2 scavanged plasma samples were collected in the same participant [▬] and had values of 1.6 ng/mL and 14.4 ng/mL.

11.5.1. Analysis of Pharmacokinetics

As previously described, a one compartment PK model described the clindamycin concentration vs. time data well [12]. For the base model, use of WT was compared with FFM, NFM, and LBW. WT resulted in the lowest objective function value: 7157.9, WT; 7173.0, FFM; 7173.0, NFM; and 7164.8, LBW. Thus, all additional covariate models were evaluated after accounting for body size using WT. Consistent with previous findings, after accounting for body size, use of a sigmoidal maturation function with postmenstrual age (PMA) resulted in the largest objective function value drop (-115.6 points). Thereafter, albumin (ALB) and alpha-1 acid glycoprotein (AAG) on V and serum creatinine on CL reached statistical significance; however, the latter was not included in the final model because its retention during the backward elimination step was largely a result of one influential individual (with a value of 3.4 mg/dL). Therefore, the final model included body weight, a sigmoidal maturation relationship between PMA and CL, and exponential relationships between ALB and AAG on V: CL (L/h) = 13.8*(WT/70)^0.75*(PMA^2.83/(39.5^2.83+PMA^2.83)); V (L)= 63.6*(WT/70)*(ALB/3.3)^-0.83*(AAG/2.4)^-0.25. Maturation reached 50% adult CL values at ~40 weeks PMA. Diagnostic plots, including visual predictive checks, for the final model are shown in the PK report, see Appendix 16.4.4.

Empirical Bayesian estimates (EBEs) obtained from the final model were stratified by obese status and age (Table 11-2). For the >6-12 years and >12 years age categories, statistically significant differences were observed in the absolute (i.e., non-weight normalized) V estimates (P<0.001). Half-life of elimination was also significantly different, but only for the >6-12 years age group (P=0.01). No other statistically significant differences were observed between obese and non-obese children.

Table 11-2

Comparison of Empirical Bayesian Estimates for the Final Model Using TBW to Correct for Body Size.

Previously recommended clindamycin dosing regimens [12] were simulated using the final population PK model described herein and compared to simulated adult exposure (70 kg) following 600 mg every 8 hours intravenously. The median (2.5th, 97.5th percentiles) simulated steady-state area under the concentration versus time curve from 0 to 8 hours (AUC0-8,SS) when stratified by age-based dosing were: 44.2 mcg*h/mL (14.0-146.0), 12 mg/kg every 8 hours if 2-6 years; 44.8 mcg*h/mL (14.4-144.0), 10 mg/kg every 8 hours if >6-12 years; and 48.6 mcg*h/mL (15.4-156.0), 10 mg/kg every 8 hours if >12 years. Median exposure of these dosing regimens were within 25% of the median observed in a 70 kg simulated adult receiving 600 mg intravenously every 8 hours: 44.7 mcg*h/mL (13.6-134.2), which was comparable to those previously reported in the literature [29]. Patients that would receive greater than 900 mg following weight based dosing (>75 kg for 12 mg/kg and >90 kg for 10 mg/kg), received a maximum dose of 900 mg. Box plots of simulated AUC0-8,SS and maximal drug concentration at steady-state (CMAX,SS) stratified by age is shown in Figures 11-1 and 11-2, respectively.

Figure 11-1

Box Plot of AUC_0-8,SS Following Age-Based Clindamycin Dosing and Stratified by Obese Status. The upper and lower whiskers extend to the highest and lowest points that are within 1.5*interquartile range.

Figure 11-2

Box plot of C_{MAX, SS} Following Aged-Based Clindamycin Dosing and Stratified by Obese Status.

After correcting for protein binding and using an optimal dosing regimen, the simulated unbound, steady-state clindamycin concentrations were above a minimum inhibitory concentration of 0.12 mcg/mL for at least half the dosing interval in >95% of participants across age groups (Table 11-3).

Table 11-3

Percentage of Participants with Simulated Unbound Concentrations Above a Minimum Inhibitory Concentration (MIC) of 0.12 μg/mL.

11.5.2. Statistical and Analytical Issues

11.5.1. By-Participant Displays

By-participant displays (i.e. “patient profiles”) are presented in Figure 14.4.1. For each participant, values over the course of the study from first study procedures through the end of study treatment is presented.

11.6.1. Drug-Drug and Drug-Disease Interactions

Drug-drug and drug-disease interactions were not analyzed in this study.