Early Phase Clinical Trials in Patients With Hepatic or Renal Impairment

FDA^1,2 and EMA^3,4 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.

Key open questions

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_B) and rate of ultrafiltration (Q_UF).

Taking into account the special hemodialysis parameters such as the extraction coefficient by the dialyser (E), hemodialysis clearance (CL_HD), and the amount of drug removed by dialysis (A_R), 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.

Dosing adjustment recommendations

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_max. 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.

Conclusions

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.

References

1. Guidance for Industry “Pharmacokinetics in Patients with Impaired Renal Function”, FDA, March 2010, Rev. 1 (Draft)
2. Guidance for Industry “Pharmacokinetics in Patients with Impaired Hepatic Function”, FDA, May 2003
3. “Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function”, EMA, August 2005
4. “Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function”, EMA, August 2014
5. Phase I studies and early drug development, Gellie Gieaser; FDA CP1 presentation

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