I am very honored to be receiving this award recognition and offer great thanks for those who supported my activities promoting better use of antiretrovirals in pediatrics through application of clinical pharmacology. I am especially grateful given the award's namesake, Sumner Yaffe, MD, who was a trailblazer in pediatric clinical pharmacology, pushing the now-accepted mantra that “children are not miniature adults.” His persistent effort resulted in recognition and understanding at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the FDA that pediatric clinical pharmacology was essential to the safe and effective use of drugs in children. His persistence led to the establishment of the NICHD Pediatric Pharmacology Research Unit (PPRU) Network in 1994, where I was fortunate to learn from him in my journey on conducting pediatric clinical pharmacology trials to better understand drug effects and to help establish rational dosing and inform pediatric drug labeling. I am also very honored to be recognized by PPA, a critical organization in promoting rational therapeutics in children. In a perfect world, we would be able to easily and directly incorporate science-based medicine into the drug therapy for children. However, in reality there are frequently extenuating circumstances and important differences between clinical situations and clinical trial results that limit our ability to directly apply existing literature to drug treatment for infants and children. Therefore, it is critically important that groups such as PPA exist to provide leadership in bridging these gaps and integrating emerging scientific findings with “real-world” patient and logistic factors, including drug formulation, administration methods, co-morbidities, and concomitant medications, to allow for delivery of optimal pediatric therapy.I consider myself extremely fortunate to have had amazing opportunities early in my career, along with supportive leadership that allowed me to participate in clinical pharmacology research focusing on expanding our understanding of HIV treatment in pediatrics. After completing my fellowship training, one of my early pharmacy responsibilities included performing therapeutic drug monitoring at the University of California–San Diego Medical Center. At this academic teaching institution, I quickly encountered James Connor, MD, a pediatric infectious disease specialist who actively directed the pediatric antiviral assay laboratory. This laboratory performed quantitative drug concentration determinations in biologic fluids for pediatric clinical trials. These results were being sent only to study sponsors as raw concentrations but no pharmacaokinetic (PK) modeling or interpretation were performed or shared with participating investigators. Unfortunately, in that era (pre–Best Pharmaceuticals for Children's Act), study sponsors had little incentive to analyze these pediatric data themselves. So the results would sit in their data warehouses, underanalyzed, making only minimal contributions to pediatric therapeutics. In discussions with Dr Connor, we saw this as a missed opportunity and thought about how we could help create more knowledge from the pediatric PK data being generated from our laboratory. We focused on applying population PK (PopPK) methods to the drug concentration data. This approach was well suited for the sparse PK data available from many pediatric clinical trials. Population PK also has the desirable feature of promoting the unifying of analyses of raw data across studies so that data can be leveraged from multiple small pediatric PK studies to produce more robust PK parameter estimates. Our PopPK activities led to a National Institute of Allergy and Infectious Diseases (NIAID) grant award as a pharmacology laboratory to support the Pediatric AIDS Clinical Trials Group. In our proposal not only did we include drug concentration measurements but we also proposed incorporating PopPK analysis methods into subsequent pediatric HIV trials. We were initially funded in 1992 and have been continuously funded for 30 years. Shortly thereafter we broadened our aim in pediatric clinical pharmacology by submitting a competitive grant proposal for the NICHD PPRU Network and were selected as one of the initial sites. As a PPRU site, we joined the PPRU Network, which included a cadre of expert pediatric clinical pharmacologists with complementary expertise and experience to design and conduct the trials needed to promote the safe use of drugs in infants and children across many diseases. I was able to take the lessons learned from the broad PPRU experience into my pediatric clinical pharmacology studies of HIV therapies.Treatment and prevention of HIV infection is one of the recent great medical success stories; however, it is my belief that it is substantially underappreciated, particularly with regard to pediatric HIV infection. Pediatric AIDS is a disease in which children, particularly infants, do not behave like “miniature adults” with respect to drug PK, pharmacodynamics (PD), and disease progression. The natural course of HIV infection in adults presents as a self-limited viral infection that slowly depletes key immune cells, but opportunistic infections and progression to full-blown AIDS takes a decade after HIV infection to develop. In contrast, newborns infected with HIV in utero who do not receive HIV antiretroviral therapy have an approximate 50% mortality rate during their first few years of life because of HIV ravaging the immature immune system. Once we were able to detect the HIV virus in blood and remove HIV-tainted blood from distribution, pre-adolescent pediatric HIV infection occurred almost exclusively via mother-to-child transmission (MTCT). This can occur in utero in the peripartum period or during breastfeeding. Prior to the availability of HIV antiretrovirals (ARVs), HIV-infected mothers transmitted HIV to their babies about 25% to 40% of the time. The initial perinatal ARV study, Pediatric AIDS Clinical Trials Group (ACTG) 076, studied maternal ZDV administration during pregnancy, at delivery, and then post-partum in infants for 6 weeks. It demonstrated1 a two-thirds reduction in infant infection despite having almost no effect on HIV viremia in the mother. Subsequently, NVP, an ARV with a much longer half-life than ZDV, was shown2 to reduce MTCT with only 1 to 2 infant doses. Combination therapy with newer ARVs used to treat the mother during pregnancy frequently suppresses HIV viremia below the limit of detection (HIV RNA <50 copies/mL).3,4 Prenatal care with effective ARV treatment and maternal virologic suppression can limit in utero and peripartum transmission. Furthermore, the use of infant formula instead of breast milk can prevent HIV transmission through breastfeeding. Maternal virologic suppression combined with infant ARV prophylaxis for the first 4 weeks of life have driven infant HIV infection rates down to near zero in developed countries. In low-resource settings, infant formula is unaffordable and formula-fed babies are deprived of the critical immunologic benefits from breast milk, which is urgently needed in low-resource settings. Thus, not only is infant formula unaffordable, the lack of potable water and limited sanitation infrastructure mean that the use of infant formula leads to increased gastrointestinal infection morbidity. Remaining areas of need to prevent infant HIV infection include universal access to pre-natal care, including HIV testing and treatment, and better approaches to preventing transmission during breast-feeding. So while we have the tools and knowledge to prevent infant HIV infections worldwide, there are still more than 150,000 new pediatric HIV infections annually.5 Where the cost, availability, and risks of formula feeding are high, breastfeeding is recommended for HIV-exposed babies, and it continues to represent the major route of HIV transmission in pediatrics. Thus, as I will discuss later, additional efforts are focused on reducing HIV transmission in breastfed infants. This task is hindered by the limited availability of suitable ARV formulations for neonates. While there are more than 20 individual ARVs and many more ARV combinations with FDA approval for use in adults, less than 10 are approved for use in newborns, and most of these represent older, less potent agents first approved in adults more than 20 years ago.I came into pediatric clinical pharmacology with the belief that PopPK analysis with computer data analysis programs such as NONMEM was a powerful approach to help describe ontogeny and age effects on drug disposition, fostering the design of optimal dosing recommendations. In addition, using limited sampling design PopPK can also leverage existing information across studies. However, to develop rational pediatric therapeutics from these data, we desperately need appropriate formulations combined with an expanded understanding of a drug's age-defined PD. Pediatric dosing regimens can be designed to match target plasma trough drug concentrations or AUC values found to be effective in adults, but allometric principles inform us that one cannot simultaneously find a pediatric dose to match both trough drug concentrations and AUCs from adults forin pediatric patients. If one designs a pediatric dosing regimen to match the adult AUC, then one typically generates a higher peak and lower trough in pediatrics than are seen in adults. On he other hand, pediatric dose regimens designed to match adult troughs result in higher peak concentrations and larger AUCs than are seen in adults. Thus, a clear understanding of the drug's PD and the target exposure metric (e.g., peak, trough, AUC) driving the clinical responses will determine the the optimal pediatric ARV dose – a dose designed to match the AUC in adults is different than a dose designed to match the trough in adults. As we are all well aware, pediatric formulation and food effects need to be considered in the design of optimal orally administered pediatric therapies. Differences in formulations and how a drug is administered can have a huge effect on drug PK and therapeutic success in the pediatric patient. While we are slowly moving away from liquid formulations toward chewable and dispersible tablets for infant and young child ARVs, these non-adult formulations rarely have the same absorption properties as the corresponding original solid oral dosage forms designed for adults.Because many antibiotics and antivirals are primarily renally eliminated, I took great interest in understanding the ontogeny of renal function and its variability in neonates. There were detailed descriptions of renal function maturation when I was starting to study ARVs in infants. However, few were derived in a manner that helped describe the individual components driving variability in renal ARV clearance that could be directly integrated into PopPK models. Most infant PK studies were performed during the first 1 to 2 weeks of life, and data were much more limited beyond this period of life and rarely incorporated markers of renal function. Infant dosing guidelines supported by these studies based their dosing on weight, post-natal age (PNA), gestational age (GA) at birth, or post-menstrual age (PMA), but they failed to provide appropriate guidance on dosing for older term infants and infants with elevated serum creatinine (SCR) and renal dysfunction. This led us to study the factors of vancomycin renal clearance during the first 2 years of life.6 In this population, SCR is initially highly correlated with GA at birth, while SCR continues to be highly correlated with PNA and PMA in older infants. We found SCR was a better predictor of vancomycin clearance than was either GA or PNA. We also studied ampicillin and aminoglycoside renal clearance early in life, looking to characterize both early and later changes in renal clearance.7,8 Using a single exponential PNA function or a sigmoid Emax PMA model we described overall maturation of clearance, though both approaches had some bias in renal clearance in the first few days of life.We are exploring a bi-exponential function to describe maturation of renal clearance, which shows promise in characterizing both early and later changes in renal clearance with less bias. This approach is consistent with the shape of changes in SCR during the first year of life.9The first available ARV for treating HIV infection in adults or children was ZDV. As a single agent, ZDV has limited potency, and therefore a maximum tolerated dose approach was used during its development. This resulted in a relatively high adult dose of 200 mg 5 times a day that often resulted in mild, but tolerable, toxicity. Zidovudine is metabolized by uridine glucuronyl transferase, and thus, determining pediatric dosing required extrapolating from the adult dose while incorporating the maturation pattern of this enzyme system in infants and young children. We incorporated a PopPK strategy into the landmark pediatric study, Pediatric ACTG 152, that evaluated ZDV and didanosine (DDI) for treatment of HIV infection in over 800 pediatric patients.10 Our work characterized significant increases in ZDV metabolism over the first 3 years of life.11 Of note, ZDV was associated with increased toxicity and poor growth in this younger age group (<3 years of age), who had higher ZDV concentrations compared with older children. We found that ZDV exposure (AUC) correlated with the early fall in hemoglobin concentrations. The study also demonstrated important efficacy differences between ZDV and DDI that were contrary to results obtained from adult studies. In adults, ZDV was found to be clinically superior to DDI. However in the Pediatric ACTG 152 trial, children did not behave like “miniature adults,” as DDI demonstrated superior efficacy compared with ZDV, in large part because of the higher ZDV toxicity seen in infants.10Preterm birth represents another important challenge to designing optimal ARV therapies for children. Preterm birth is associated with increased risk of MTCT. After ZDV became commonly used for preventing MTCT, we found plasma elevated ZDV concentrations in 15 preterm babies higher than had been previously observed in term infants.12 This was expected because uridine glucuronyl transferase activity is reduced with prematurity.To develop dosing guidance in preterm infants for the first 6 weeks of life we conducted a study of ZDV that included a therapeutic drug monitoring component. We offered real-time assessments of ZDV concentrations to encourage participation and increase infant safety. Through our PopPK analysis, we found that ZDV clearance was initially lower in preterm infants than had been previously observed in term infants during the first week of life. We also found significant differences in ZDV clearance based on GA at birth; those born between 26 and <30 weeks GA had lower and slower increase of ZDV clearance over time (PNA) than did those born at 30 to <36 weeks GA (Figure).13 Simulations based on the resulting PopPK model were used to develop GA- and PNA-specific dosing recommendations for preterm infants that were incorporated in the US Department of Health and Human Services HIV treatment guidelines.Low-dose NVP has also been shown to prevent MTCT and has utility resource–limited settings as well. One or 2 infant NVP doses has been shown2 to prevent peripartum transmission. Repeated daily doses of NVP to infants can reduce HIV transmission to breastfed infants with less than a quarter of the dose needed to treat infant HIV infection.14 Additional PK, safety, and dosing information in term and preterm infants is needed to develop NVP treatment. We recently conducted 2 studies15,16 to address these knowledge gaps. Nevirapine is metabolized by several cytochrome (CYP) P450 isoforms and induces its own metabolism. This makes predicting steady-state PK from single-dose PK studies very difficult and complicates the development of rational dosing strategies that are safe and can be easily implemented in newborns. We found that infants born between 34 and 37 weeks GA required a 33% dose reduction to achieve similar NVP concentrations to full term infants.16To address the lack of ARV PK and safety data in preterm infants we initiated International Maternal, Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Study P1106 (ClinicalTrials.gov, NCT02383849). This study was designed to determine the safety and PK of ARVs and isoniazid in low birth weight infants. It took an opportunistic approach to collecting ARV and isoniazid PK and safety information from infants receiving these drugs as part of their clinical care over the first 6 months of life. Population PK modeling of NVP data from this study and others is currently being performed to help develop optimal NVP dosing recommendations in low birth weight infants that include incremental dose increases to account for increased metabolism from auto-induction and maturation.15Many pregnant women are taking ARVs that do not yet have infant formulations and thus cannot be studied by direct administration to infants. In this setting we are collecting washout PK from infants born to these mothers to determine the initial infant clearance to help design future PK studies once infant formulations do become available. We have studied both RAL and DTG washout PK to characterize neonatal PK on the first days of life, when drug metabolism would be considered to be at its lowest level of activity.17,18 We found a 10-fold increase in RAL metabolism shortly after birth, which required 2 dose increases during the first few weeks of life to maintain therapeutic concentrations.17Another consideration with ARV dosing in infants is how to achieve adequate and consistent absorption for newer ARVs (e.g., LPV, EFV, RAL, ATV) during the first 6 months of life. Many of these agents are lipophilic, making their absorption dependent on solubility within the gastrointestinal tract and influenced by food intake. Lopinavir is rapidly metabolized by CYP 3A, resulting in poor bioavailability and a very short half-life. To address these PK liabilities, LPV has been co-formulated with RTV, which inhibits LPV metabolism, improving bioavailability and extending the drug's half-life to allow twice-daily dosing of the combination. In the first 2 weeks of life LPV/RTV has been associated with substantial hemodynamic and renal adverse events. This may in part be due to the high ethanol and propylene glycol content of the liquid pediatric formulation. Regardless of the exact mechanism for these toxicities, the FDA issued a boxed warning against LPV/RTV use in the first 2 weeks of life and below 42 weeks PMA.19 Interestingly, slightly older infants, but those still less than 6 months of age, require larger mg/m2 doses than do older infants and other populations to achieve adequate LPV concentrations.20 To better understand some of these differences, we conducted a PopPK analysis of LPV across infant studies that included infants and found that reduced absorption in young infants is the likely cause of this larger dose requirement.21More recently we have evaluated LPV/RTV use in term and pre-term infants shortly after initiating therapy to determine how to dose LPV/RTV in this setting. This is a critical age for HIV treatment, as ARV options are limited and rapid control of viral replication can have long-term immunologic benefits. The LPV/RTV was evaluated in 25 infants (72% low birth weight) who were enrolled between 1 and 2 months of age, with sparse PK sampling collected for 6 months. The LPV/RTV treatment was safe and well tolerated, including in the 12 infants who initiated LPV/RTV before 42 weeks PMA. Large variability in LPV/RTV absorption was observed with a corresponding lower AUC at first PK collection, with absorption increasing with PNA.22 In the first month of life impaired absorption of LPV/RTV can be a huge barrier to optimal HIV therapy in term infants. In the PETITE study using a 4:1 formulation of ABC/3TC/LPV/RTV, the LPV AUC was 3.5 mcg·hr/mL, well below the study target of 20 to 100 mcg/mL and the typical adult value of 80 to 90 mcg·hr/mL.23 The results from these studies confirm that when we are administering drugs orally, we must consider not only the maturation of liver metabolism pathways but also age effects on bioavailability (F) because of changes in gut solubility, gut metabolism and drug transporters because exposure is driven by the apparent clearance (CL) (CL/F), not CL.Pediatric ARV drug therapy currently involves a combination of at least 3 different ARVs. Fixed-dose combinations (FDCs) have been developed to simplify administration, reduce pill burden, and enhance adherence. While these FDCs have been easy to construct in adults using typical doses and their drug component dose ratios, there are additional complexities in pediatrics. In young infants, the rates of maturation are different for different elimination pathways. So the drug component ratio of the ideal drug doses based on single drug studies in newborns may not be the same as the ratios in older pediatric patients. In addition, the ages at which dose changes are needed also differ, and implementation of these changes in low-resource settings necessitates the use of low-complexity algorithms. To address some of these challenges I have worked through the World Health Organization Pediatric Antiretrovirals Working Group in the development of weight-band dosing of ARVs in infants and children (see Table). These weight-band dose recommendations are designed to help standardize pediatric dosage forms and provide target tablet strengths for generic manufacturers to produce. They also institute growth-driven dose increases at the same weight thresholds for all ARVs rather than calculating milligram-per-kilogram, doses for each agent, requiring care providers to round this dose to determine the best available strength to use. Weight-band dosing and FDCs introduce some minor differences from the ideal labeled dose for each agent, but the trade-off of simplified and consistent dosing is, in my opinion, worth this minor deviation.While I have focused thus far on age, maturation, and weight as they relate to ARV dosing, these factors are not the only sources of ARV PK variability in pediatrics. For several years, EFV was the drug of choice in adults because of its potency, long half-life, and ability to be co-formulated with TFV and FTC into a once-daily single Atripla tablet. While EFV was also commonly used in older children and adolescents, difficulties in developing a liquid formulation prevented its use in children under 3 years of age. In resource-limited settings where ARV alternatives are limited there is a greater need for EFV. Unlike many ARV alternatives, EFV has limited drug-drug interactions with anti-tuberculosis (TB) drug therapy and can be used in HIV-TB–co-infected children. Efavirenz is primarily metabolized by CYP 2B6, and while significant differences have been observed in adults and children based on their CYP 2B6 genotype, the drug is FDA approved at a single-dose level, regardless of CYP 2B6 genotype metabolizer status.24 We performed an international multicenter study of EFV in HIV-infected children between 3 and 36 months of age with and without concomitant TB infection. Efavirenz was administered as opened capsules, and blood samples were obtained as dried blood spots and plasma, with the dried blood spots used to monitor EFV concentrations in real time, with dose adjustments made where necessary. Based on prior limited PK data (REF Capparelli EV, Robbins B, Rathore M, Britto P, Hu C, Weinberg A, Browning R, Hazra R, McKinney RE)25. Pediatric Population Pharmacokinetics of Efavirenz (EFV) – High Dose Requirements in Infants Likely Due to Reduced Absorption. Presented at ICAAC 2010 A1-2008), EFV weight-band dosing was developed using opened capsules, with large infant doses used to overcome anticipated low bioavailability in this population. A dose of 400 mg was used for 10-kg infants, which represents two-thirds of the adult 600-mg dose. Originally the CYP 2B6 genotype was determined for a planned post hoc analysis, but grossly excessive EFV concentrations observed in poor metabolizers required the study to be modified to analyzing participants' CYP 2B6 genotype prior to initiating EFV therapy. Genotype-specific dosing was used, with homozygous CYP 2B6 poor metabolizers receiving 25% of the EFV dose used in heterozygous and homozygous extensive CYP 2B6 metabolizers. With CYP2B6-specific dosing, EFV targets were met, with all subsequent poor EFV metabolizer infants achieving EFV concentrations in the target range.26,27 Monte Carlo simulations indicated that separate EFV dosing recommendations are essential for normal vs poor metabolizers. In contrast, TB co-infected infants receiving the known CYP inducer rifampin with isoniazid do not need additional dose modifications, as the change in CL/F is minor. Thus, a simplified dosing strategy using the same dose, regardless of TB co-infection status, is recommended.28Recently, broadly neutralizing monoclonal antibodies against HIV (bNAbS) have been studied as a novel approach to prevent and treat HIV infection. These bNAbS have the advantage of good safety and tolerability in newborns and prolonged duration of action after a single administration. Because they have no affinity for CYP enzymes and work by binding viral proteins that are not classical ARV targets, they exhibit minimal classical drug-drug interactions and no cross-resistance with existing classes of ARVs. They are not metabolized by classic liver drug–metabolizing enzymes nor are they eliminated renally but rather undergo lysosomal proteolysis through the reticuloendothial system just like endogenous immunoglobulins. Like other antibodies, their metabolism can be shielded from proteolysis by binding to the Neonatal Fc Receptor protein (FcRn) within the lysosome. Modifications of the constant region of bNAbs can enhance their binding to FcRn and reduce metabolism by more than 50%. We evaluated the first bNAb in newborns VRC01, shortly after completion of the adult study and without the standard march down through older pediatric age groups.29 We combined the VRC01 PK results from newborns with PK data from adult studies to construct a PopPK model of VRC01 that was then used for Monte Carlo simulations.30 From this analysis we developed a VRC01 dosing strategy for infants that would maintain high bNAb concentrations when used to treat acute HIV infection (IMPAACT Study 2008, NCT03208231). Aggressive treatment with bNAbs early during infection may limit the size of the viral reservoir and promote adaptive immunity, including endogenous antibody production against HIV. These effects may foster long-term benefits, allowing reduction in ARV intensity that could include a “functional cure” in a subset of infants in which the infant's own immunologic response may keep HIV suppressed without ARVs.By modifying 2 amino acids in the constant region, antibody lysosomal degradation can be retarded and a bNAb's half-life increased without affecting antigen-antibody interactions. A modified long-acting version of VRC01, VRC01LS, has been developed and studied in infants. VRC01LS demonstrates a much slower decline in serum concentrations than does VRC01 in adults, but this LS modification in infants had a smaller impact on the apparent half-life. This is most likely due to the rapid growth in infants having the same dilutional effect with both VRC01 and VRC01LS.31 However, VRC01LS PK still supports the concept that a single VRC01LS dose given shortly after birth and another dose at 3 months of age would maintain protective bNAb concentrations against sensitive viruses for 6 months. Additional doses could be given at 3-month intervals for babies who continue to risk HIV acquisition via breastfeeding beyond 6 months. We have recently evaluated VRC01LS in combination with another bNAb,10-1074, in young children infected with HIV from birth but successfully suppressed with combination ARVs.32 The early safety and PK results of this combination are encouraging, indicating multiple bNAbs can be used together safely to enhance the breadth of desired antiviral coverage.We have made tremendous strides in our understanding of HIV infection and the clinical pharmacology of ARVs to optimize prevention and treatment in pediatric patients. Many of the current barriers to elimination of MTCT and pediatric HIV relate to health care delivery system limitations and other resource-related issues. Additional pediatric clinical pharmacology studies of HIV therapies are ongoing to devise simplified strategies and enhanced early antiviral responses, which can result in lifelong health benefits in HIV-infected infants.