Narine Baririan, Pharm. D

Antibodies, also called immunoglobulins (Igs), are large proteins used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. Several monoclonal antibody (mAbs) drugs have been approved, or are at the late stage of clinical development within various therapeutic indications. The amount of mAbs making it to the market will continue to increase thanks to their characteristics, including good solubility and stability, long persistence in the body, high selectivity and specificity of action, and low risk of toxic metabolites.

	However, mAbs still have complex pharmacokinetic (PK) and pharmacodynamic (PD) properties compared to small chemical molecules. These include poor bioavailability, slow distribution, both linear- and non-linear elimination processes, and other factors influencing PK and PD such as immune reactions/immunogenicity.

	Before planning a first-in-human (FIH) study, robust preclinical data should be available providing sufficient insight into the full PD pathways, and used to select the most appropriate animal species from both PK/PD and safety considerations. Challenging steps in designing FIH studies with mAb drugs, therefore remain, and the appropriate selection/exclusion criteria of healthy volunteers, a carefully selected safe and appropriate starting dose; the choice of dose escalation steps to achieve the goal of FIH study; the planning of sufficient and correct follow-up procedures; and the safety monitoring necessary, considering both the short term site related reactions and delayed PD effects.

	In addition, due to incidents in the past, authorities look more rigorously toward mAbs, considering many of them as high-risk medicinal products. A sound early clinical development plan, including appropriate justifications, might help regulatory bodies with their evaluation of what they view as high risk.   

	Initial monoclonal antibody drugs were generated from mouse and rat hybridomas, and these first-generation antibodies had only limited clinical success because of their short half-lives and high immunogenicity. Several approaches have been developed to humanize these rodent antibodies, and technological advances during the past four decades have allowed mAbs to be developed and produced at commercial scale. The FDA and the European Medicines Agency (EMA) have approved many mAbs in various therapeutic areas, and it is estimated that several hundred mAbs are currently in development.

	As noted above, (PK/PD) analyses are essential steps in the early drug development process. Antibody drugs often exhibit PK/PD properties that are much more complex than those typically associated with small-molecule drugs (i.e., organic compounds with molecular weight <1,000 Da).

	Most of the marketed antibodies are labeled for intravenous administration, but several mAbs are under development or have been approved for intramuscular or subcutaneous injections. The subcutaneous route is of growing interest as an administrative method, however, factors affecting the bioavailability, such as catabolic first-pass clearance, subcutaneous transport processes, and translation of subcutaneous animal data to humans require further research.

 Oral administration of mAbs for systemic therapy is not indicated, because of their size, polarity, and gastrointestinal degradation, which preclude adequate bioavailability.

	The bioavailability of mAbs after intramuscular or subcutaneous administration varies between 50% and 80%.

 As a rule, after subcutaneous administration, biologicals with molecular weight >16kDa are largely absorbed into the lymphatic system (slow absorption rate), while those <2kDa are absorbed into the blood circulation.

mAbs and their derivative drugs are large biologicals with a molecular weight of around 150kDa; therefore, after intramuscular or subcutaneous injection, absorption of these drugs into the lymphatic system proceeds slowly, and the time to reach maximal plasma concentrations typically ranges from two to eight days.

	There is a relatively new interest in the development of aerosolized mAbs for pulmonary delivery, as the lungs have a very large surface area and a high perfusion rate. In addition, pulmonary epithelial cells are known to express neonatal Fc-receptor (FcRn), which may facilitate efficient systemic absorption of antibody delivered to the lung. However, similar to, or even more than, intramuscular or subcutaneous administration, the feasibility of pulmonary delivery of mAbs is limited to those with very high dose potency, as only small volumes of fluid can be administered.

	Analysis of antibody distribution is much more complicated than the analysis of the distribution of most small molecule drugs. mAbs are often designed to bind with high affinity to tissue sites containing the target antigen; however, because of their large size and hydrophilic nature, they have a slow distribution to peripheral tissue.

 Unlike small molecules, the paracellular movement of biologics is mainly via convective transport instead of passive diffusion.

	Higher mAb concentrations have been observed in body tissues that are highly perfused with relatively leaky vascularization such as the spleen, liver, and bone marrow; but very little distribution to the brain. This may be because of the blood-brain barrier with its “tight junctions,” the rapid turnover of brain intestinal fluid, or potentially because of the active involvement of the FcRn in mAb efflux from brain tissue.

Experimentally, and by using a physiologically-based PK (PBPK) model, the tissue to blood ratio of mAbs was estimated to be in the range of 0.1 to 0.5, but only 0.02 for the brain.

	If the target of the mAb is localized in tissue, slow and/or low distribution to tissue from the systemic circulation may be an obstacle to achieving clinical responses. Alternatively, antibody fragments, consisting of only an antigen-binding part (Fab fragments) or single-chain variable fragments, can cross the blood-tissue barrier more easily and, hence, are less hindered by this “binding-site barrier” and poor distribution compared to intact mAbs.

	Additionally, for macromolecular protein drugs such as mAbs, it is likely that a significant fraction of drug elimination occurs from tissue sites that are not in rapid equilibrium with plasma. In such situations, non-compartmental analysis of plasma data will lead to an underestimation of the distribution volume (V

). When significant drug elimination occurs from “peripheral compartments,” it is not possible to obtain precise estimates of V

 from analysis of plasma data alone. Plasma concentrations may be used to define the range of possible values for the distribution volume, but the determination of tissue concentration by biopsies or imaging techniques would provide more insight into distribution.

	Because of their molecular size, mAbs are not generally excreted into urine, but are metabolized to peptides and amino acids that can be re-used in the body for the 

 synthesis of proteins, or are excreted by the kidney. A few mAbs with a molecular weight <69 kDa are mainly cleared by renal excretion, and thus the clearance of these biologics can be compromised in patients with renal impairment.

 Several elimination mechanisms are reported to be involved in mAbs elimination, of which the three most commonly observed are proteolysis by the liver and the reticuloendothelial system, target-mediated elimination, and nonspecific endocytosis.

	First, phagocytic cells such as macrophages and monocytes are expected to play a role in the elimination of mAbs, as they are also key factors in the elimination of endogenous IgG. Internalization and subsequent degradation of IgG by lysosomes in these cells occurs predominantly after binding of the Fc part of the antibody to Fcg-receptors expressed on these cells.

	A second elimination route is degradation of the mAb within the target cell after internalization and subsequent intracellular degradation in its lysosomes. For mAbs targeting an antigen located on cells, degradation by target cells after binding of the Fv-part to the target antigen (target-mediated elimination) is probably the most important elimination route. As this route is saturable as a result of the confined amount of target antigen, non-linear elimination has often been reported for mAbs.

The rate of uptake and elimination of antibodies by target-mediated pathways is a function of dose, the expression level of the target, the kinetics of receptor internalization, and intracellular catabolism.

	Finally, mAbs may also be taken up into cells in different tissues by non-specific pino- or endocytosis. After uptake in the slightly acidic environment of the endosomes in endothelial cells, the immunoglobulins bind to the FcRn. After binding, the IgG-FcRn complex is transported back to the cell surface, where it is released again into the circulation. In contrast, unbound IgG is degraded into amino acids by lysosomes present in the cell.

 In the absence of target-mediated drug clearance, most IgG-based mAbs exhibit long half-lives, typically three or four weeks, mainly as a result of FcRn-mediated antibody recycling.

	Another distinction between small molecules and biologics is that biologics can be immunogenic, leading to the formation of neutralizing anti-drug antibodies (ADA). It has been shown that the change in elimination rates resulting from immunogenicity may be either increased or decreased, depending on the number of sites on the therapeutic mAb that the endogenous anti-mAb are directed against. Because of individual differences in the immune response to mAb administration, it is difficult to predict how immune response influences the elimination rate of therapeutic mAbs and whether a change in the elimination rate has clinical implications.

The degree of humanization, route of administration, duration of therapy, and dose level can also impact immunogenicity.

	A complication with any ADA response found in preclinical species is that it does not accurately predict the ADA response in humans. Therefore, it is essential to assess the ADA response in FIH studies and evaluate this information with respect to its impact on PK and/or PD, when possible. If there is an effect on PK (and related to that to PD), it is frequently that the elimination of the affected mAb drug is increased, resulting in a reduced systemic exposure; this additional clearance pathway should be considered when establishing a PK or PK/PD model, and when designing the further clinical evaluation studies.

	Since the 1980s, mAbs are increasingly being incorporated into clinical practice as therapeutic options, particularly in oncology and immunology, and several are still under development. While these targeted therapies are predicted to be highly selective and specific, protein-based drugs such as mAbs, like all drugs, can have unpredictable safety profiles.

	One of the reasons for the revised EMA guidance released in 2007 was a FIH trial in 2006 with a new mAb drug.

 All subjects receiving the first dose of active drug TGN1412, a superagonist mAb against CD28, developed a life-threatening, severe adverse reaction, caused by an uncontrollable cytokine release. The maximum recommended starting dose (MRSD) was, nevertheless, determined by the conventional allometric approach from the no-observed adverse effect level (NOAEL) with a large safety factor of 160, resulting in 0.1 mg/kg. However, when using the receptor occupancy to reinvestigate this dose, it was found that 0.1 mg/kg would elicit greater than 90% receptor occupancy. So, in this situation, not only was the pharmacodynamic effect unacceptably high, producing a cytokine storm, the increased receptor occupancy could also have altered the pharmacokinetics of the antibody by decreasing its clearance, thereby further increasing the peak concentration and prolonging its effect.

	This tragic incident highlighted the importance of, and difficulties in, selecting the safest MRSD in FIH studies with mAbs. One of the lessons learned from this tragedy is that once receptor occupancy starts to increase, the PD and PK response to further dose escalations becomes non-linear. The TGN1412 incident led to the recommendation that the MRSD should also be calculated based on the minimal anticipated biological effect level (MABEL). It is important to determine in preclinical studies whether target-mediated elimination occurs, which should be considered when deriving the MABEL.

	MABEL is useful for protein drugs because it defines a dose at which receptor occupancy is low. Per the revised EMA guideline, the FIH doses need to be calculated from both NOAEL and MABEL, and the lowest value is recommended for the clinical trial.

For biotherapeutics, such as mAbs, with potential agonistic modes of action on key body systems, no more than 10% receptor occupancy is proposed as starting dose in a FIH trial.

For mAbs with antagonistic actions, a higher receptor occupancy is needed for a pharmacological effect, and, therefore, a starting dose inducing higher than 10% occupancy may be acceptable. Importantly, the selected starting dose for a FIH trial, as well as the desirable highest pharmacological active doses, should be justified, considering target saturation by mAbs and systemic PK behavior.

	Also, according to the draft EMA guideline published in 2016, specific attention should be paid to the preclinical development program of mAb drugs as a support to FIH studies.

Data on the functionality of additional antibody domains in animals should be present; for example, the Fc receptor. The demonstration of pharmacological relevance of the animal model(s) for the mAbs under development is crucial, and may include comparison with humans via tissue cross-reactivity studies using human and animal tissues.

	Suh and colleagues published a review article in 2016 covering the results of FIH studies with mAbs from 1990 to 2013, with access to the starting dose estimation.

 The NOAEL-based approach was still the most commonly used MRSD determination method for FIH studies with mAbs (21.5%). The publication year was significantly associated with the choice of MRSD determination method. The proportion of FIH studies that did not report the MRSD determination method was very high, at more than 50%, in 1990-2007, while the MABEL-based approaches were more frequently used in 2011–2013, with an incidence of more than 30%. The increase in adoption of MABEL for the more recent studies reflects the impact of the TGN1412 incident and the EMA guideline that followed. Although the MABEL-based approach produced an MRSD lower than those derived by the other approaches, the average number of dose escalation steps was similar.

	Many mAbs are intended to treat different oncological pathologies, and, therefore, FIH studies in that indication may have some other particularities. The one-sixth highest non-severely toxic dose has been introduced as an alternative method in estimating MRSD, not resulting in unacceptable toxicities in FIH (not exceeding the maximum-tolerated dose) and reducing dose escalation steps.

	Independent of the safety profiles of mAbs, once the oncological indication is obvious, the FIH may be performed in patients rather than in healthy volunteers, as a treatment option in the absence of an effective alternative treatment. Consequently, the challenge to avoid the under-dosing of patients is added to the starting dose estimation and dose escalation determination process.

	Another challenge when developing a mAb is determining the optimal route of administration. Site reactions are a common side-effect of antibodies when administered subcutaneously or per infusion and can lead to interruption and termination of a FIH study. The implementation of prophylactic measurements such as H1- and H2-blockers, steroids, paracetamol, and the prolongation of the infusion might help to avoid reactions. Any implementation of such measures in early phase trials substantially influences the further development of the compound.

The best approach would, therefore, be to foresee a continuous observation of patients during the first hours after the injection of new mAb with a well-established treatment schema in an experienced clinical pharmacology unit.

	Another factor that should be taken into account when designing the FIH trial of mAb drugs is the possible delayed PD effect related to duration of target inhibition or target-mediated PK profile. Sufficiently long follow-up of subjects should be foreseen to monitor possible delayed adverse reactions. Human terminal elimination half-life predicted by modeling and simulation (M&S) and/or by using physiologically-based PK (PBPK) modeling may support the estimation of the duration of the long-term follow-up period in trials with mAbs administered as single or multiple doses in early phases.

	If we follow the EMA draft guideline (2007),

Medicinal products are defined as potential 

 when there are concerns that serious adverse reactions in FIH clinical trials may occur”

. In the recent EMA guidance for FIH trials (2017), “

” during the FIH studies with any new compound and “

” are discussed without highlighting the “

Even if mAbs are in clinical research for more than 30 years, they are often still considered high risk because of uncertainties regarding the mode of action, the nature of the target, and/or the relevance of animal models. However, this is not always the case, for example when:

		The mAb mechanism of action is fully investigated with primary and secondary targets.

		Target-mediated elimination is of minor role.

		A mAb drug is on the market with similar physicochemical and PK/PD properties.

		Advanced M&S is assisting all the steps of preclinical and clinical development. 

	Regulatory agencies and research ethics committees rightly insist on the use of a “sentinel” group approach in FIH, particularly in the single dose part, comprising one active-treated and one placebo-treated subject at the start of the study, and at each dose increment. This approach is mandatory in non-standard situations, such as when drugs are first-in-class, if their anticipated physiological effects are potentially profound, and when non-linearity in PK/PD is suspected. This is likely to apply for most mAbs. The intention is to identify any highly repeatable serious adverse event in a single subject rather than being faced with an entire cohort in trouble, as happened in the TGN1412 trial.

 Which data to analyze from the sentinel group, the time needed to observe them before proceeding, staggered dosing, and whether this should be done in every escalation step are further challenges that will need to be solved by clinical and PK/PD experts.

	Additionally, there are certain data which need to be reviewed on a case-by-case basis, such as the individual mAb drug properties, any available preclinical safety and PK/PD data, and the subject population. After each sentinel group, a safety review committee, or more complete data monitoring committee (including PK, PD and other available data review) may be required. The added value of reviewing the PK and PD data at interim stages will depend on the individual mAb PK/PD profile-assessing among other things, the mechanism of action, drug half-life, and target-mediated distribution and elimination. The same review approach is applicable during dose escalation and decision-making steps in a FIH studies with mAb drugs.       

	The PK and PD of mAbs are complex and differ from those of non-mAb drugs. There are numerous PK factors that should be taken into account when designing and running an early phase clinical trial, especially if an antibody has a novel mechanism of action. The growing shift from NOAEL to MABEL, in particular, has the potential to reduce the risks to trial subjects being dosed with a novel mAb for the first time. Careful trial design, informed by knowledge of an antibody’s PK peculiarities, is essential if the study is to run both smoothly and safely.

, PharmD, is Clinical Pharmacology and PK Expert, SGS - Clinical Research

	1. W Wang, EQ Wang and JP Balthasar; Monoclonal antibody pharmacokinetics and pharmacodynamics, 

	2. Wolfgang F. Richter, Suraj G. Bhansali and Marilyn E. Morris; Mechanistic Determinants of Biotherapeutics Absorption Following SC Administration, 

	3. Liang Zhao, Tian-hua Ren, Diane D Wanf; Clinical pharmacology considerations in biologics development, 

	4. Ron J. Keizer, Alwin D.R. Huitema, Jan H.M. Schellens and Jos H. Beijnen; Clinical Pharmacokinetics of Therapeutic Monoclonal Antibodies, 

	5. Tang L, Meibohm B; Pharmacokinetics of peptides and proteins. Pharmacokinetics and pharmacodynamics of biotech drugs. Weinheim: Wiley-VCH Verlag GmbH and Co, 2006: 17-43

	6. Lobo, E.D., Hansen, R.J. and Balthasar, J.P; Antibody pharmacokinetics and pharmacodynamics. 

	7. Liming Liu; Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins; 

	8. Josiah T. Ryman and Bernd Meibohm; Pharmacokinetics of Monoclonal Antibodies; 

	9. Guideline on Immunogenicity assessment of therapeutic proteins; May 18, 2017; EMEA/CHMP/BMWP/14327/2006 Rev 1

	10.   Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products; July 19, 2007; EMEA/CHMP/SWP/28367/07

	11.  Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products; July 20, 2017; EMEA/CHMP/SWP/28367/07 Rev. 1

	12.  Vijay Sharma and John H McNeill; To scale or not to scale: the principles of dose extrapolation; 

	13.  Hoon Young Suh, Carl CPeck, Kyung-Sang Yu, Howard Lee; Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013; 

	14.  Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products; July 20, 2017; EMEA/CHMP/SWP/28367/07 Rev. 1

	15.  Zou P, Yu Y, Zheng N, Yang Y, Paholak HJ, Yu LX, Sun D; Applications of human pharmacokinetic prediction in first-in-human dose estimation; 

	16.  Guideline on development, production, characterisation and specification for monoclonal antibodies and related products; July 21, 2016; EMA/CHMP/BWP/532517/2008

	17.  Aaron R. Hansen et al; Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials; 

	18.  Adrian M. Senderowicz; Information Needed to Conduct First-in-Human Oncology Trials in the United States: A View from a Former FDA Medical Reviewer; 

, published online first March 9, 2010; DOI: 10.1158/1078-0432.CCR-09-2766

	19.  Guideline on requirements for first-in-man clinical trials for potential high-risk medicinal products; March 22, 2007; EMEA/CHMP/SWP/28367/2007 Corr.

	20.  J. M. Ritter; More on first-in-man studies; 

Articles

Outlining the unique pharmacokinetic factors that should be considered when designing and running early stage clinical trials for monoclonal antibodies.

Monoclonal Antibodies: Clinical Pharmacology Keys

There are several pharmacokinetic factors and peculiarities that should be considered carefully when designing and running first-in-human (FIH) studies for monoclonal antibodies.

Monoclonal Antibodies: Clinical Pharmacology Knowledge in Support of FIH and Early Development

 guidance is intended to help companies evaluate the need for conducting pharmacokinetic (PK) studies in renal impaired and hepatic impaired patients, and to provide guidance on how to best assess the influence of renal impairment (RI) or hepatic impairment (HI) on the pharmacokinetics of an investigational drug.

	A large number of prescription drugs are at some point likely to be administered to RI or HI patients, and should therefore be investigated in that population. However, the available guidelines in this area are either relatively old (EMA and FDA guidelines for HI are from 2005 and 2003, respectively); still in a draft version (FDA guideline for RI since 2010); or not sufficiently detailed (EMA guideline for RI, 2014). It is this lack of available and up-to-date clarity regarding the design, conduct and data analysis of early phase RI or HI trials in the guidelines which leaves some key questions that must be addressed on a case-by-case basis at a very early stage of the clinical development.

	The first issue that needs to be clarified is whether the study should be a full or reduced design. A decision tree for determining when and how RI or HI studies should be conducted is given in the FDA guidelines, and shown in Figures 1 and 2, below. As a general approach, when renal or hepatic elimination is not the major route of elimination of the parent drug and/or active metabolites, a “reduced” study can be sufficient in RI and HI, respectively. Accordingly, the sponsor has the option of conducting a reduced or “full” study, and the choice should be based on the PK properties of the drug, including all data from in vitro, pre-clinical and clinical studies.

	The FDA also advises that if a reduced PK study shows a substantial effect on PK in the patients with RI, a full RI study should be conducted. While for patients with HI, the findings in the moderate category in a reduced study would be applied to patients with a mild Child-Pugh category, and dosing in the severe category would generally be contraindicated.

	Moreover, FDA and EMA guidelines are not consistent in the definition of reduced design for RI studies. According to the FDA, End Stage Renal Disease (ESRD) subjects who are not undergoing dialysis should be compared to matched healthy volunteers, while according to the EMA, patients with severe RI should be compared to matched healthy volunteers. This poses a challenge for the recruitment of ESRD patients not under dialysis as this type of patient is quite difficult to find. As a consequence, a full study (including all the stages of RI) is often preferred by sponsors in order to meet the timelines, and also to avoid a possible restart of a full study in case of a substantial effect on PK in patients with RI in the reduced study. Additionally, the minimum number of subjects required in reduced design (at least eight per group) is higher than in full design (at least six per group).

Statistical considerations and matching strategy

	The control group of healthy volunteers should be comparable (matched) to the RI/HI patient population with respect to age, gender, race and weight. Depending on the drug under investigation, other factors with significant potential to affect the PK should also be taken into consideration. Matching prevents confounding by increasing precision of estimates (reduction in standard errors). Since in RI/HI studies, the sample size is often small and there could be an association between the matching factor and drug PK, matching factors should be controlled in the statistical analysis of PK parameters, which is not often the case.

	There are no recommendations in the guidelines about the matching method, but two strategies are commonly used. When individual matching is used, controls are matched to patients one by one for each of matching criteria. The advantages of this method are the simultaneous recruitment of patient-healthy volunteer pairs, and the potential to reuse healthy volunteer data among RI/HI groups. The most important advantage however, is the guarantee of statistically robust results compared to the only disadvantage of the need of more healthy volunteers compared to other matching strategies. The second matching is group matching, and in this approach all patients with RI/HI are completed, and a healthy volunteer will be selected (matched) based on the defined distribution (percentiles) of each matching criteria. The advantage of this method is that a lower number of healthy volunteers is required, which should be equal to the number of patients in one group of RI/HI patients.

	However, this method cannot be considered as the first choice in early phase RI/HI trials because it is less statistically robust when comparing PK results between RI/HI groups and Healthy volunteers.

Particularities of the dialysis effect assessment in RI trials

	Dialysis may affect the PK of a drug to an extent that dosage adjustment is needed. In general, a study of the effect of dialysis on PK may be omitted if the drug is unlikely to be administered to ESRD patients treated with dialysis, or if the dialysis procedure is unlikely to result in significant elimination of drug or active metabolites.

	If dialysis is assessed, PK should be studied in such patients under both dialysis (DTP) and non-dialysis (IDTP) conditions, to determine the extent to which dialysis contributes to the elimination of the drug and potentially active metabolites. Venous blood samples during IDTP, and blood from both arterial and venous sides of fistula, during DTP should be collected. Drug concentration in dialysate, total plasma proteins and drug free fraction in arterial and venous sides should be measured at several time points during the DTP. Some key hemodialysis parameters should also be reported, such as blood flow through the dialyser (Q

	Taking into account the special hemodialysis parameters such as the extraction coefficient by the dialyser (E), hemodialysis clearance (CL

), and the amount of drug removed by dialysis (A

), will provide answers to the main questions:

		Was the drug removed through the hemodialyser?

		How effectively can the dialyser remove the drug from the blood?

		Is the drug removed through the membrane?

	Common PK parameters have to be calculated during the IDTP, as well during the DTP, using drug concentration data from venous side. This will allow the comparison of the PK behavior of the investigational drug between IDTP and DTP.

	The principal objective of an early phase RI/HI study is to advise on dosing recommendations. When applicable, it is also important to point out in dosing recommendations that HI/RI does not alter a drug’s PK. If the effect of HI/RI on the PK of the drug is obvious, dosage adjustments should be recommended in the Clinical Study Report of the early phase study. It is also possible that the effect of HI/RI on the PK is only partial, i.e., significantly altered only in one or more groups but not in all groups compared to healthy volunteers.

	To reach a conclusion about the significance of altered PK, a confidence interval approach, rather than a significance test, is preferred in HI studies according to available FDA guidelines. The no-effect boundaries are defined prior to conducting the studies, based on information available for the investigational drug PK, or a standard 90% confidence interval of 80-125% for AUC and C

. The FDA recognizes that providing evidence showing that a PK parameter remains within an 80-125% no-effect boundary would be very difficult given the small numbers of subjects usually entered into HI studies. If a wider boundary is fixed, it should be supported clinically (no safety issue) and confirmed by formal sample size calculation based on inter-subject variability observed in healthy volunteers. However, it may be more probable to conclude that there is no need for dose adjustment with the wider boundaries; therefore, this choice should be taken into consideration when observing the PK properties of the drug.

	In RI studies, a significance test is used without statistical flexibility, which can often make it difficult to draw conclusions about the RI effect on the drug PK with the low number of subjects. The conclusion in this case should be evidence-based, and if needed confirmed by a PK/PD study in a much larger patient population. Extra caution is therefore needed when developing a drug with narrow therapeutic index (NTI) and some general approaches to estimate the exact dose adjustment are available using relatively simple equations. Since some conditions should be fulfilled to apply those equations and since they are still not optimized, modeling and simulation (M&S) are highly recommended. M&S takes into account drug PK/PD properties, administration particularities and indicates the best approach of dosing adjustment.

Recommendations to correctly interpret results

	Several scientific review articles have concluded that there is remarkable variation in definitions and recommendations, and a lack of scientifically relevant interpretation and description of methods, making the available results from early phase RI and HI trials unsuitable for clinical use. RI and HI are very complex pathologies, so the particular patho-physiological changes in these patients, together with the PK properties of the drug, should be carefully considered when interpreting the observed results. Some scientific recommendations to be considered when interpreting the PK results are presented below:

		An understanding of the fundamental PK principles related to renal and hepatic clearances of drug will be helpful to correctly interpret the results of PK observations in RI/HI trials.

		Extra caution is needed when investigating a drug with NTI in patients with RI/HI.

		For some particular drugs, PD changes in patients with RI/HI are possible without the potential contribution of alteration in the PK behavior of the drug.

		Severe hepatic dysfunction is usually accompanied by RI (hepato-renal syndrome).

		Hemodialysis in ESRD patients may remove the drug, uremic toxins, thereby complicating drug effect in patients with RI.

		Patients with RI/HI require multiple medications, therefore, the influence of concomitant medications on investigational drug PK should be assessed.

		It is mandatory to investigate plasma protein binding in the evaluation of the effect of RI/HI on drug PK.

		The activity of various Phase I/II metabolic enzymes or cellular transporters may be differently altered in HI.

		Several gastrointestinal dysfunctions may result to the altered absorption of an orally administered drug in HI.

		Child-Pugh classification is simple and often not sensitive enough to distinguish mild from moderate HI.

		Drug metabolism alteration may differ according to the etiology of HI.

	At an early stage of drug development, studies in RI/HI special populations are almost always required for drugs with systemic absorption. Conclusions from early phase RI/HI trials are very difficult to draw, are variable, and often are not clear. The best solution is the development of a robust study design by clinical and scientific experts. The study design, as well the interpretation of results, should be based on PK/PD properties of the drug and with an understanding of the fundamental on the PK principles related to RI and HI pathologies.
	
	

		Guidance for Industry “Pharmacokinetics in Patients with Impaired Renal Function”, FDA, March 2010, Rev. 1 (Draft)

		Guidance for Industry “Pharmacokinetics in Patients with Impaired Hepatic Function”, FDA, May 2003	

		“Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function”, EMA, August 2005	

		“Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function”, EMA, August 2014	

		Phase I studies and early drug development, Gellie Gieaser; FDA CP1 presentation

	Narine Baririan, Pharm.D, PK Expert, SGS Life Sciences - Clinical Research

Studies in Hepatic and Renal Impaired special populations have almost always required drugs with systematic absorption resulting in unclear conclusions. A solution for this would be a study design based on pharmokinetic properties that incorporates principles of Hepatic and Renal Impaired pathologies.

Narine Baririan, Pharm. D

Articles

Monoclonal Antibodies: Clinical Pharmacology Keys

Monoclonal Antibodies: Clinical Pharmacology Knowledge in Support of FIH and Early Development

Early Phase Clinical Trials in Patients With Hepatic or Renal Impairment