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Smith PB, Smith MJ, Gonzalez D, et al. Safety and Pharmacokinetics of Multiple-Dose Intravenous and Oral Clindamycin in Pediatric Subjects with BMI ≥ 85th Percentile [Internet]. Bethesda (MD): National Institute of Child Health and Human Development (US); 2015 Oct 15.
Safety and Pharmacokinetics of Multiple-Dose Intravenous and Oral Clindamycin in Pediatric Subjects with BMI ≥ 85th Percentile [Internet].
Show details7.1. Background Information
Over the past decade, community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a leading cause of hospitalization for children and adolescents in the United States [1]. Consequently, the use of antimicrobial agents active against MRSA has become more prevalent [2]. Specifically, the use of clindamycin among children hospitalized with Staphylococcus aureus infections increased from 21% in 1999 to 63% in 2008. At the same time, rates of childhood obesity have continued to remain high. Recent national data demonstrate that 17% of children aged 2–19 years in the United States are obese (body mass index [BMI] ≥ 95th percentile) and 12.3% are morbidly obese (BMI ≥ 97th percentile) [3]. Obese patients have a greater likelihood of complications from infectious diseases and are at increased risk of developing Staphylococcus aureus infections.
Clindamycin, a semisynthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin [4], is approved by the U.S. Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with respiratory tract, female pelvis and genital tract, and skin and soft tissue infections with susceptible bacteria, including streptococci, pneumococci, and staphylococci. Clindamycin is also approved in adults for septicemia and intra-abdominal and serious infections with susceptible anaerobic bacteria [5].
Clindamycin is approximately 90% protein-bound. It is metabolized by the liver and excreted via the liver, bile, and kidneys. Impaired renal function modestly decreases the elimination of clindamycin; however, dosage adjustment is not required with renal dysfunction [4]. Clindamycin phosphate (intravenous [IV] formulation) is rapidly converted to active clindamycin which has an elimination half-life of about 3 hours in adults and 2.5 hours in children [5]. The drug penetrates well into all tissues, with the exception of the brain and cerebral spinal fluid. It is actively taken up and concentrated within the phagocytic cells. Clindamycin binds to the 50S subunit on the bacterial ribosome and inhibits protein synthesis by interfering with the formation of initiation complexes, thus inhibiting exotoxin production [4]. Clindamycin exhibits time-dependent killing, and efficacy is correlated with the time clindamycin concentrations exceed the minimum inhibitory concentration of the pathogen of interest. A summary of clindamycin serum concentrations in non-obese children is found in Appendix 16.1.1.
Variability in serum and tissue concentrations has been reported in obese patients [4]. The underlying premise is that this is due to physiologic changes that alter a drug’s volume of distribution (V) and body clearance (CL) [6,7]. Thus, obese patients may be dosed inappropriately if fixed or “adult” doses are used (under-dosed) or if weight-based dosing is used (over-dosed) [6,7]. Because critically ill obese patients with infections are reported to have a worse outcome than non-obese patients [8], it is imperative to determine if the disposition of and response to clindamycin may be altered compared to healthy-weight children with an infection. In addition, sub-therapeutic drug concentrations may increase the development of resistant organisms. Thus, it is important to perform pharmacokinetic (PK) and pharmacodynamic (PD) studies in the obese pediatric population to ensure that these patients are being optimally dosed with medications designed to treat infections. There are no currently available PK (or PD) data to guide clindamycin dosing in obese pediatric or adult patients.
7.2. Scientific Rationale
Selection of the correct drug dose and dose regimen is the most important decision in ensuring optimal pharmacotherapy. Defining an optimal regimen requires a clear understanding of the drug’s PK, PD, and, for many compounds, pharmacogenomic (PG) profiles. Understanding these characteristics for drugs used in pediatrics is imperative to determine optimal dose regimens across the pediatric age continuum.
Clinically, drug dosing in pediatrics is individualized to age by basing the drug dose on a patient’s body weight and the dose interval on the functional capacity of the drug’s clearance pathways. This approach assumes, though inaccurately, that a drug’s V and body CL are directly proportional to a patient’s body weight. Despite this lack of proportionality, the majority of pediatric patients favorably respond to weight-based drug dosing. However, as the potency of newer drugs increases and the need for more precise drug dose regimens expands, better-defined dose regimens based on careful assessment of the drugs’ integrated PK-PD-PG profiles across the pediatric age continuum, including term and preterm infants, are needed [9]. Complicating this paradigm are the substantially increasing numbers of children and adolescents who are obese, and even morbidly obese, and the lack of data on disposition in the obese population. Clinical trials of new drugs focused on FDA labeling exclude obese patients, leaving the determination of dosing regimens in the obese for post-marketing, often investigator-initiated studies.
7.2.1. Antibiotic Dosing Regimens Based on PK-PD Modeling
Prior to our understanding of the integrated PK-PD characteristics for antibiotic drugs, antibiotic dosing regimens were mostly based on perceived maximum tolerated doses, often related in some manner to the target pathogen minimum inhibitory concentration (MIC). Integration of an antibiotic’s PK with PD allows for the determination of the optimal dose regimen across the spectrum of antibiotic drugs [10,11]. In addition, this more quantitative approach permits comparisons of different antibiotic drugs for a specific infection and far more accurate predictability of patient response. The specific antibiotic PK-PD characteristic used to predict outcome (i.e., bacteriologic eradication) appears to be mostly dependent on whether the drug’s bacterial killing is concentration- or time-dependent. Clindamycin is most often described as a “time-dependent antibiotic with moderate persistent effects,” and as such, the best predictor of bacterial killing appears to be the ratio of the area under the clindamycin (free, unbound) drug concentration time curve (AUC) divided by the targeted pathogen MIC (i.e., fAUC/MIC) [11]. To accurately determine this pivotal PK-PD parameter, what is needed is a comprehensive understanding of the drug’s PK profile across the age spectrum while incorporating the spectrum of pathophysiologic changes and differing body habitus. For clindamycin, these data are not available.
7.2.2. Clindamycin Pharmacokinetics
Limited published clindamycin PK data exist in children [12]. In neonates, clindamycin elimination is delayed compared with older infants and children—mean elimination half-life (t ½) values of 8.7 vs. 3.6 hours, respectively [13,14]. Regardless of age group studied, variability was observed in clindamycin t ½, V, and systemic CL. In addition, some studies report variable serum clindamycin concentrations (bioactivity) following parenteral dosing [13,15]. Despite this variation in drug disposition, which is observed in both children and adults, bioactive serum clindamycin concentrations remain therapeutic following routine parenteral (intramuscular, IV) or oral dosing. Considering that clindamycin is used to treat infections caused by susceptible pathogens responsible for infectious diseases regardless of patient age, pediatric clindamycin development strategies need only focus on the drug’s safety and PK profile to ensure similar systemic exposure. Available clindamycin PK data support close similarity for clindamycin systemic exposure (i.e., bioactive serum clindamycin concentrations and AUC) in older infants, children, and adults following comparable mg/kg doses [13, 15–20]. As noted above, clindamycin PK in premature and full-term infants is, as expected, different than that observed in older patients [13,14]. This foundation of data also underscores the importance of studying clindamycin disposition in the obese pediatric patient.
Clindamycin is extensively bound to plasma protein, primarily to alpha-1 acid glycoprotein, and, with the exception of the brain or cerebrospinal fluid, effectively penetrates body tissues and fluids. The drug is metabolized primarily by the cytochrome (CYP) P450 isoenzyme CYP3A4 to two primary, antimicrobial active metabolites, a sulfoxide and to a lesser extent N-demethylclindamycin [21]. Although only limited data are available for current clindamycin pediatric dosing regimens, the regimens employed clinically have been used for decades with apparent success. Nevertheless, clindamycin optimal dosing regimens in pediatrics remain unknown. Furthermore, the influence of obesity on clindamycin disposition is unknown and may have a far greater negative impact on patient outcome due to ill-defined, clinically extrapolated dosing.
7.2.3. Drug Dosing and Obesity
Data defining optimal drug dosing in the obese and morbidly obese adult patient are very limited and virtually non-existent in pediatrics. Drug dosing on total body weight (WT) in the obese patient has the real risk of overdosing the patient, resulting in an increased incidence of adverse effects, while dosing on ideal body weight (IBW) can lead to serious under-dosing. In obese adults, IBW is increased by 20–40%, which is unaccounted for when using the many mathematical formulas available to calculate dosing based on a person’s IBW. This deficiency may partially explain the inaccuracy of drug dose regimens for obese patients based on IBW formula estimations [22–27].
The influence varying degrees of obesity have on important physiologic functions across the age continuum in pediatrics is unknown. In adults, sparse data suggest that obese adults may have altered tissue blood flow rates due to inherent differences in blood flow to lean (greatest amount) and adipose tissue, impaired cardiac function, and alterations in phase I and II metabolism. Although intuitive, one might assume that a drug’s V would be increased in obese patients for lipophilic compounds, though in fact, for the few drugs assessed, the V is highly variable. Similarly, CL is also highly variable in the obese population, underscoring the need to determine drug disposition characteristics not only across the age continuum but also with increasing degrees of obesity [22–25]. No such data are available for the pediatric patient, but these data combined underscore the need to critically assess a drug’s disposition relative to age and body habitus. Furthermore, for antibiotics whose efficacy is dependent on achieving effective concentrations at the infectious site, interfaced with the organism, optimal dosing in the obese pediatric patient must be defined [6,7].
7.3. Potential Risks and Benefits
7.3.1. Potential Risks
Risks of Blood Draws
There are small risks to blood sampling, usually some pain/discomfort with the blood stick. Every effort was made to avoid additional (to standard of care) sticks for this study by timing clinical blood draws to coincide with timed samples when possible and the use of existing IV lines when feasible for the blood draws.
Risks of Clindamycin
From the FDA label and review of the literature, the following are adverse reactions of clindamycin: antibiotic-associated colitis; pseudomembranous colitis; abdominal pain; nausea; and vomiting; hypersensitivity reactions (maculopapular rash and urticaria have been observed during drug therapy; generalized mild-to-moderate morbilliform-like skin rashes are the most frequently reported of all adverse reactions; rare instances of erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin; a few cases of anaphylactoid reactions have been reported). Organ systems that are affected include skin and mucous membranes (pruritus, vaginitis, and rare instances of exfoliative dermatitis have been reported); liver (jaundice and abnormalities in liver function tests have been observed during clindamycin therapy); renal system (although no direct relationship of clindamycin to renal damage has been established, renal dysfunction as evidenced by azotemia, oliguria, and/or proteinuria has been observed in rare instances); hematopoietic (transient neutropenia [leukopenia] and eosinophilia have been reported; reports of agranulocytosis and thrombocytopenia have been made; no direct etiologic relationship to concurrent clindamycin therapy could be made in any of these instances); local reactions (pain, induration, and sterile abscess have been reported after IM injection and thrombophlebitis after IV infusion); musculoskeletal (rare instances of polyarthritis have been reported); cardiovascular (rare instances of cardiopulmonary arrest and hypotension have been reported following too rapid IV administration). There is minimal additional risk to the participants who are receiving clindamycin as part of their routine medical care.
7.3.2. Known Potential Benefits
Participants may have benefited from the use of the study drug; otherwise, participation in this study had no other potential benefits for participants. The results of this study may benefit overweight and obese children in the future who require clindamycin therapy.
7.4. Best Pharmaceuticals for Children Act
The Best Pharmaceuticals for Children Act (BPCA) mandates the National Institutes of Health (NIH) to prioritize therapeutic areas in critical need for pediatric labeling, sponsor pediatric clinical trials, and submit these data to FDA for consideration for labeling changes. The three studies discussed in this report (NICHD-2012-CLN01, NICHD-2011-POP01 and NICHD-2012-STA01) are conducted in accordance with Section 409I of the Public Health Service Act; as such, the results from this research are being submitted to the FDA for review and may be used in negotiated labeling changes. These research studies are contractually supported by the NICHD. The NICHD awarded a contract to the Duke Clinical Research Institute (DCRI) to establish a Pediatric Trials Network (PTN) in order to facilitate trial design for studies supported by NIH. A separate contract is awarded to The Emmes Corporation to serve as the BPCA Data Coordinating Center (DCC).
7.5. Data Sources
This Clinical Study Report presents study results from the NICHD-2012-CLN01 study. The final PK model was developed using data derived from three different studies in order to develop a robust population PK model that accounts for size- and age-dependent changes in drug disposition. Clinical trial data from the following studies were used in the analysis:
7.5.1. NICHD-2012-CLN01: Safety and Pharmacokinetics of Multiple-Dose Intravenous and Oral Clindamycin in Pediatric Subjects with BMI ≥ 85th Percentile (NICHD-2012-CLN01)
This prospective multi-center trial was conducted under protocol NICHD-2012-CLN01 within the Pediatric Trials Network (PTN) to characterize the PK of intravenous clindamycin in overweight and obese children and adolescents. This study was conducted under the same IND as NICHD-2012-STA01 (IND 115,396) described in Section 7.5.3. The CLN01 protocol (Appendix 16.1.1) was a prospective, multi-center, open-label, multiple-dose PK study of intravenous and oral clindamycin and enrolled children ages 2 – <18 years of age with body mass index (BMI) ≥ 85 percentile for age. The first participant was enrolled in August 8, 2013, and the last participant completed in August 15, 2014.
7.5.2. NICHD-2011-POP01: Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care
This prospective multi-center trial is being conducted under protocol NICHD-2011-POP01 within the PTN to characterize the PK of understudied drugs, including clindamycin, administered to children <21 years old per standard of care by their treating caregiver. This study is being conducted through the ‘Opportunistic’ study mechanism under IND 113,645. This protocol (Appendix 16.4.1) is enrolling participants under multiple drugs of interest, each of which are administered to children per standard of care. Only participants enrolled for clindamycin as the drug of interest are included in the analyses for this CSR. The first participant was enrolled for clindamycin on December 20, 2011, and data were included from samples analyzed before July 15, 2015. This study is actively recruiting, and enrollment for clindamycin was ongoing at the time of CSR finalization.
7.5.3. NICHD-2012-STA01: Pharmacokinetics of Antistaphylococcal Antibiotics in Infants
This prospective multi-center trial is being conducted under protocol NICHD-2012-STA01 within the PTN to characterize the PK of rifampin, ticarcillin-clavulanate, clindamycin in infants. This study was conducted under IND 115,396. This protocol (Appendix 16.4.2) is a multiple center, open-label, PK study and enrolled hospitalized infants that were <121 days postnatal age and < 30 weeks gestational age. The clindamycin arm of this study was closed to further enrollment on April 11, 2014 after meeting its enrollment target. Participants were either receiving clindamycin as per standard of care or were administered the study drug as part of the study. The first participant was enrolled for clindamycin in February 8, 2013, and the last participant completed in March 8, 2014.
7.5.4. Summary of Data Sources
As outlined above, in this CSR, the final PK model for this CSR was developed using data from three different studies, namely, NICHD-2012-CLN01, NICHD-2011-POP01, and NICHD-2012-STA01. Table 7-1 presents the data sources for this study report.
Table 7-1
Data Sources for the PK and Safety Analysis.
7.6. Structure for this Clinical Study Report
As explained in Section 7.5, this report analyzes and discusses PK and safety data from NICHD-2012-CLN01. Sections 8, 9 and 10 of this report will cover the investigational plan and overall study population from the NICHD-2012-CLN01 study. Section 11 of this report will cover the PK analysis of data from all three studies (NICHD-2012-CLN01, NICHD-2011-POP01, and NICHD-2012-STA01). Section 12, which covers the safety analysis, will include safety data from the NICHD-2012-CLN01 study alone.
- INTRODUCTION - Safety and Pharmacokinetics of Multiple-Dose Intravenous and Oral...INTRODUCTION - Safety and Pharmacokinetics of Multiple-Dose Intravenous and Oral Clindamycin in Pediatric Subjects with BMI ≥ 85th Percentile
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