He then again admirably discusses the term πρωτότοκος as it is four times employed by the Apostle
Now that we have arrived at the understanding of these words, no one could any longer hesitate as to the other passages, for what reason He is the first-born, either “of the dead,” or “of the creation,” or “among many brethren.” For all these passages refer to the same point, although each of them sets forth some special conception. He is the first-born from the dead, Who first by Himself loosed the pains of death, that He might also make that birth of the resurrection a way for all men. Again, He becomes “the first-born among many brethren,” Who is born before us by the new birth of regeneration in water, for the travail whereof the hovering of the Dove was the midwife, whereby He makes those who share with Him in the like birth to be His own brethren, and becomes the first-born of those who after Him are born of water and of the Spirit: and to speak briefly, as there are in us three births, whereby human nature is quickened, one of the body, another in the sacrament of regeneration, another by that resurrection of the dead for which we look, He is first-born in all three:— of the twofold regeneration which is wrought by two (by baptism and by the resurrection), by being Himself the leader in each of them; while in the flesh He is first-born, as having first and alone devised in His own case that birth unknown to nature, which no one in the many generations of men had originated. If these passages, then, have been rightly understood, neither will the signification of the “creation,” of which He is first-born, be unknown to us. For we recognize a twofold creation of our nature, the first that whereby we were made, the second that whereby we were made anew. But there would have been no need of the second creation had we not made the first unavailing by our disobedience. Accordingly, when the first creation had waxed old and vanished away, it was needful that there should be a new creation in Christ, (as the Apostle says, who asserts that we should no longer see in the second creation any trace of that which has waxed old, saying, “Having put off the old man with his deeds and his lusts, put on the new man which is created according to God,” and “If any man be in Christ,” he says, “he is a new creature: the old things are passed away, behold all things have become new:”) — for the maker of human nature at the first and afterwards is one and the same. Then He took dust from the earth and formed man: again, He took dust from the Virgin, and did not merely form man, but formed man about Himself: then, He created; afterwards, He was created: then, the Word made flesh; afterwards, the Word became flesh, that He might change our flesh to spirit, by being made partaker with us in flesh and blood. Of this new creation therefore in Christ, which He Himself began, He was called the first-born, being the first-fruits of all, both of those begotten into life, and of those quickened by resurrection of the dead, “that He might be Lord both of the dead and of the living,” and might sanctify the whole lump by means of its first-fruits in Himself. Now that the character of “first-born” does not apply to the Son in respect of His pre-temporal existence the appellation of “Only-begotten” testifies. For he who is truly only-begotten has no brethren, for how could any one be only-begotten if numbered among brethren? But as He is called God and man, Son of God and Son of man—for He has the form of God and the form of a servant, being some things according to His supreme nature, becoming other things in His dispensation of love to man—so too, being the Only-begotten God, He becomes the first-born of all creation,— the Only-begotten, He that is in the bosom of the Father, yet, among those who are saved by the new creation, both becoming and being called the first born of the creation. But if, as heresy will have it, He is called first-born because He was made before the rest of the creation, the name does not agree with what they maintain concerning the Only-begotten God. For they do not say this—that the Son and the universe were from the Father in like manner—but they say, that the Only-begotten God was made by the Father, and that all else was made by the Only-begotten. Therefore on the same ground on which, while they hold that the Son was created, they call God the Father of the created Being, on the same ground, while they say that all things were made by the Only-begotten God, they give Him the name not of the “first-born” of the things that were made by Him, but more properly of their “Father,” as the same relation existing in both cases towards the things created, logically gives rise to the same appellation. For if God, Who is over all, is not properly called the “First-born,” but the Father of the Being He Himself created, the Only-begotten God will surely also be called, by the same reasoning, the “father,” and not properly the “first-born” of His own creatures, so that the appellation of “first-born” will be altogether improper and superfluous, having no place in the heretical conception.
Source: Against Eunomius (New Advent)