Developmental changes in physiology during childhood influence drug dosing. Failure to account for these changes leads to improper dosing, which is associated with decreased drug efficacy and safety in children. Population physiologically-based pharmacokinetic (PBPK) modeling offers the opportunity to predict optimal drug dosing based on physiologic parameters adjusted for developmental changes. PBPK models are mathematical constructs that incorporate physiologic processes with drug characteristics and genetic variances to characterize the dose-exposure relationship across the age continuum. These models integrate drug-specific (e.g., metabolism, protein binding) and systems-specific (e.g., organ size, blood flow) information to predict the effect of different factors (e.g., age, genetic variants, disease) on drug exposure. By accounting for these factors and using data from clinical trials to confirm the modeling, PBPK models can reduce the number of children needed for clinical trials while maximizing dose-based efficacy and safety. This trial will evaluate a platform to prospectively validate population PBPK models in children. The study drugs, clindamycin and Bactrim (aka TMP-SMX), are ideal candidates to evaluate population PBPK models in children due to their differing physico-chemical properties and elimination pathways. In addition, a trial of clindamycin and TMP-SMX has broad clinical applicability, as both drugs are among the most commonly used agents to treat gram-positive infections in infants and children.

NCT02475876

Conditions

1. Bacterial Infections

Interventions

1. Drug: Clindamycin
2. Drug: trimethoprim-sulfamethoxazole

MeSH:Bacterial Infections

Genetic analysis of the most important single nucleotide polymorphisms (SNPs) in the CYP3A family and CYP2C9 genes will be performed using commercially available Taqman Polymerase Chain Reactions assays for the following gene expressions: CYP3A4: rs35599367, rs2246709, rs4646437, rs2740565, rs4253728 CYP3A5: rs776746, rs10264272, rs15524 CYP3A7: rs2687133, rs2257401 CYP2C9: rs1799853, rs1057910 Subjects will be classified into homozygous and heterozygotes for allelic variants based on the genotyping results.. Number of Subjects Heterozygous for any CYP2C9 Genotype.

Genetic analysis of the most important single nucleotide polymorphisms (SNPs) in the CYP3A family and CYP2C9 genes will be performed using commercially available Taqman Polymerase Chain Reactions assays for the following gene expressions: CYP3A4: rs35599367, rs2246709, rs4646437, rs2740565, rs4253728 CYP3A5: rs776746, rs10264272, rs15524 CYP3A7: rs2687133, rs2257401 CYP2C9: rs1799853, rs1057910 Subjects will be classified into homozygous and heterozygotes for allelic variants based on the genotyping results.. Number of Subjects Homozygous for any CYP3A Family Genotype.

Genetic analysis of the most important single nucleotide polymorphisms (SNPs) in the CYP3A family and CYP2C9 genes will be performed using commercially available Taqman Polymerase Chain Reactions assays for the following gene expressions: CYP3A4: rs35599367, rs2246709, rs4646437, rs2740565, rs4253728 CYP3A5: rs776746, rs10264272, rs15524 CYP3A7: rs2687133, rs2257401 CYP2C9: rs1799853, rs1057910 Subjects will be classified into homozygous and heterozygotes for allelic variants based on the genotyping results.. Number of Subjects Homozygous for any CYP2C9 Genotype.

Genetic analysis of the most important single nucleotide polymorphisms (SNPs) in the CYP3A family and CYP2C9 genes will be performed using commercially available Taqman Polymerase Chain Reactions assays for the following gene expressions: CYP3A4: rs35599367, rs2246709, rs4646437, rs2740565, rs4253728 CYP3A5: rs776746, rs10264272, rs15524 CYP3A7: rs2687133, rs2257401 CYP2C9: rs1799853, rs1057910 Subjects will be classified into homozygous and heterozygotes for allelic variants based on the genotyping results.. Inclusion Criteria: 1. Informed consent from parent or guardian and assent from subject when appropriate 2. Require prevention or treatment of confirmed or suspected infection 3. PMA >36 weeks 4. Able to take oral drugs (TMP-SMX) 5. Sufficient IV access for study drug administration (for clindamycin) and PK sample collection (both drugs) - Exclusion Criteria: 1. History of allergic reactions to study drugs 2. Treatment with the following drugs within 24 hours prior to first dose of clindamycin or expected to receive these drugs during the treatment phase with clindamycin: - CYP3A4 inhibitors (nefazodone, fluconazole, ketoconazole, fluvoxamine, conivaptan, diltiazem, verapamil, aprepitant, ticlopidine, crizotinib, and imatinib), or - CYP3A4 inducers (rifampin, phenytoin, carbamazepine, phenobarbital, troglitazone, pioglitazone, and St. John's wort).

The efficacy and safety of antiretroviral therapy and the damage caused by chronic inflammation in the presence of the virus has recently lead to the consideration of initiating antiretroviral therapy earlier than what is required to prevent opportunistic diseases. Although there may be subtle differences, all recommended antiretroviral combinations for first-line therapy are considered equally effective. Nevertheless, treatment success requires high levels of adherence, which is linked to tolerability and the minimization of adverse effects. The genes coding the enzymes that are involved in the antiretroviral clearance pathways and the transmembrane transport of drugs are known. These genetic variations can determine the interindividual variations in plasma concentration with the same doses. Both pharmacogenomics (PG) and therapeutic drug monitoring (TDM) may contribute to the individualization of therapy in different chronic conditions through dosing optimization and are associated with a lower risk of concentration-dependent toxicity and potentially greater efficacy. The use of these strategies in the context of antiretroviral therapy is in early stage of development. Following, our main hypothesis is that PG + TDM dose adjustment of efavirenz or atazanavir in the initial antiretroviral treatment of naive patients with HIV infection is non-inferior in terms of efficacy, has improved safety, and shows a better cost/effectiveness profile than the standard approach with non adjusted doses. To evaluate our hypothesis we developed this multicenter randomized clinical trial, where patients from 4 clinical sites in Buenos Aires will be included in the protocol and randomized to standard of care (SOC) or pharmacological adaptation (PA) -PA: PG + TDM. For the pharmacogenomics determination, we developed a multiplex approach including main polymorphisms of CYP2B6, CYP2A6, CYP3A4 y ABCB1 for efavirenz; and UGT1A1, ABCB1 and CYP3A4 for atazanavir. Drug plasma levels will be analyzed with ultra-performance liquid chromatography (UPLC). The main outcomes are to establish the usefulness of PG and TDM in determining the efficacy, safety and cost/effectiveness of a first-line antiretroviral therapy containing either efavirenz or atazanavir in patients with HIV infection who have not received prior antiretroviral therapy.

NCT03385473

Conditions

1. Pharmacogenetics
2. HIV
3. Drug Monitoring

Interventions

1. Genetic: Pharmacogenomic index
2. Diagnostic Test: Therapeutic drug monitoring

PG for Efavirenz: Polymorphisms of CYP2B6 (rs3745274), CYP2A6 (rs28399433/rs8192726), CYP3A4, (rs4646437), CYP3A4*1B and ABCB1 (rs1045642).